Fused pyrimidine derivatives for inhibition of tyrosine kinase activity

ABSTRACT

The present invention relates to a novel fused pyrimidine derivative having an inhibitory activity for tyrosine kinases, and a pharmaceutical composition for preventing or treating cancers, tumors, inflammatory diseases, autoimmune diseases, or immunologically mediated diseases comprising same as an active ingredient.

The present application is a divisional of U.S. application Ser. No.13/805,183 filed Dec. 18, 2012, which is a National Stage ofInternational Application No. PCT/KR2011/004482, filed on Jun. 20, 2011,which claims the benefit of priority from Korean Patent Application No.KR 10-2010-0059686, filed on Jun. 23, 2010, the contents of which areherein incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to a novel fused pyrimidine derivativehaving an inhibitory activity for tyrosine kinases, and a pharmaceuticalcomposition comprising same as an active ingredient.

BACKGROUND OF THE INVENTION

There are many signal transduction systems in cells which arefunctionally linked to each other to control the proliferation, growth,metastasis and apoptosis of cells (William G. Kaelin Jr., Nature ReviewsCancer 5, 689, 2005). The breakdown of the intracellular controllingsystem by genetic and environmental factors causes abnormalamplification or destruction of the signal transduction system leadingto tumor cell generation (Douglas Hanahan and Robert A. Weinberg, Cell100, 57, 2000).

Protein tyrosine kinases play important roles in such cellularregulation (Irena Melnikova and James Golden, Nature Reviews DrugDiscovery 3, 993, 2004), and their abnormal expression or mutation hasbeen observed in cancer cells or autoimmune diseases. The proteintyrosine kinase is an enzyme which catalyzes the transportation ofphosphate groups from ATP to tyrosines located on protein substrates.Many growth factor receptor proteins function as tyrosine kinases totransport cellular signals. The interaction between growth factors andtheir receptors normally controls the cellular growth, but abnormalsignal transduction caused by the mutation or overexpression of any ofthe receptors often induces various cancers or autoimmune diseases suchas rheumatoid arthritis.

With regard to the roles of these tyrosine kinases, a variety growthfactors and receptors thereof have been investigated, and among them,epidermal growth factors (EGF) and EGF receptor (EGFR) tyrosine kinaseshave been intensely studied (Nancy E. Hynes and Heidi A. Lane, NatureReviews Cancer 5, 341, 2005). An EGFR tyrosine kinase is composed of areceptor and tyrosine kinase, and delivers extracellular signals to cellnucleus through the cellular membrane. Various EGFR tyrosine kinases areclassified based on their structural differences into four subtypes,i.e., EGFR (Erb-B1), Erb-B2, Erb-B3 and Erb-B4, and it is known thatEGFR activating mutations, such as L858R point mutation in exon 21 andin-frame deletions in exon 19 of the EGFR tyrosine kinase domain, arethe important cause of non-small cell lung cancer.

Gefitinib (AstraZeneca) was initially developed as a small molecule forthe inhibition of EGFR tyrosine kinases, which selectively andreversibly inhibits EGFR (Erb-B1). Erlotinib (Roche) has also similarcharacteristics. These EGFR-targeted drugs are efficacious for non-smallcell lung cancer (NSCLC) and provide therapeutic convenience forpatients with EGFR activating mutations.

However, it has been reported that the development of resistance lowersthe activity of a particular drug used in EGFR-targeted therapies. Ithas been already reported that about half of the patients administeredwith Gefitinib or Erlotinib exhibited the resistance to the drugs due tothe induction of the secondary EGFR T790M mutation (William Pao et al.,Public Library of Science Medicine, 2(3), 225, 2005, Cancer Res, 67(24),11924, 2007). Further, it has been recently found that irreversibleinhibitors to target for EGFR are more beneficial in securing excellentefficacy and overcoming the resistance development, as compared to theconventional reversible inhibitors such as Gefitinib and Erlotinib(Danan Li et al., Cancer Cell 12, 81, 2007; and Anja Michalczyk et al.,Bioorganic & Medicinal Chemistry 16, 3482, 2008). Hence, irreversibleinhibitors such as BIBW-2992 (Afatinib, Boeringer Ingelheim) (C H Mom etal., British Journal of Cancer 98, 80, 2007), PF00299804 (Dacomitinib,Pfizer) (Engelman J A, et al., Cancer Res. 67, 11924, 2007), and AV-412(AVEO Pharmaceuticals) (Tsuyoshi Suzuki et al., Cancer Sci. 98(12),1977, 2007) have been developed and are currently in the clinical stage.The compounds have been known to form a covalent bond with Cystein773(Cys773) positioned at an ATP domain of EGFR, thereby irreversiblyblocking the autophosphorylation of EGFR and thus efficiently inhibitingthe signal transduction of cancer cells (David W. Fry et al., Proc.Natl. Acad. Sci. U.S.A. 95, 12022, 1998), and exhibit higher inhibitoryactivities compared to the reversible inhibitors commercially availableas dual inhibitors of EGFR/HER-2, or pan-HER inhibitors in in vitroactivities and in various in vivo models of carcinomas (Jeff B. Smaillet al., J. Med. Chem. 42, 1803, 1999). However, the compounds may causeserious side effects such as skin rashes, diarrhea and weight loss dueto high activities to EGFR WT (wild type) present in normal cells, whenthey are administered in a dose sufficient to overcome the resistanceinduced by EGFR T790M mutations, and this has been limited theirclinical application, (Martin L. Sos, et al., Cancer Res. 70, 868,2010).

As evidenced by clinical tests of the irreversible inhibitors innon-small cell lung cancer, the compounds have exhibited improvedactivities but still weak therapeutic effects in the resistancedevelopment of cancer patients, compared to the conventional reversibleinhibitors. Accordingly, there has been a continued need to develop anovel drug that is effective in drug-resistant cancers and has noadverse side effects.

Meanwhile, there are various evidences that B-cells (B-lymphocytes) andT-cells (T-lymphocytes) play a key role in the pathogenesis ofinflammatory diseases, autoimmune diseases and/or immunity mediateddiseases.

For instance, aberrant signaling can induce deregulated B-cellproliferation and differentiation to cause all sorts of lymphomaincluding various acute or chronic lymphoid leukemia and can causeformation of autoantibodies that lead to multiple inflammatory diseases,autoimmune diseases and/or immunity mediated diseases.

Bruton's tyrosine kinase (BTK) is a member of the TEC family of tyrosinekinases, and plays an important role in B-cell activation and signaltransduction. BTK plays an essential role in B-cell signaling pathwaywhich links the B-cell receptor (BCR) stimuli on the surface of B-cellsto the response in downstream cells. Further, BTK has been known to be acritical regulator of B-cell development and mature B-cell activationand survival (Khan et al., Immunity 3, 283, 1995; Ellmeier et al., J.Exp. Med. 192, 1611, 2000; Kurosaki, Current Opinion in Immunology 12,276, 2000; Schaeffer and Schwartzberg, Current Opinion in Immunology 12,282, 2000). Thus, inhibition of BTK could be a therapeutic approach toblock B-cell mediated disease processes.

For example, it has been known that BTK-deficient mice are resistant tocollagen-induced arthritis and BTK inhibitors have been demonstrateddose-dependent efficacies in a mouse model of arthritis (Jansson andHolmdahl, Clin. Exp. Immunol. 94, 459, 1993; Pan et al., Chem. Med.Chem. 2, 58, 2007). Thus, effective BTK inhibitors may be useful in thetreatment of rheumatoid arthritis.

In addition, BTK is also expressed by cells other than B-cells that maybe involved in disease processes, i.e., bone marrow-derived mast cells.It has been reported that the antigen-induced degranulation issuppressed in BTK-deficient bone marrow-derived mast cells (Iwaki etal., J. Biol. Chem. 280, 40261, 2005). This shows that BTK could beuseful to treat pathological mast cell responses such as allergy andasthma.

Also, monocytes, in which BTK activity is absent, showed decreased TNF-αproduction following stimulation (Horwood et al. J Exp Med. 197, 1603,2003). Therefore, TNF-α mediated inflammation could be modulated by BTKinhibitors.

Furthermore, BTK has been reported to play a role in apoptosis as someof regulators (Islam and Smith, Immunol. Rev. 178, 49, 2000). Thus, BTKinhibitors would be useful for the treatment of certain B-cell lymphomasand leukemias (Feldhahn et al., J. Exp. Med. 201, 1837, 2005).

Meanwhile, T-cells play a role in transmitting signals delivered throughthe T-cell receptor (TCR) on the cell surface from antigen presentingcells into downstream effectors by the activation of intercellularvarious kinases such as janus kinases. At this time, they secretevarious interleukin (IL) or interferon-γ to activate various leukocytesas well as the B-cells. Protein kinases involved in signal transductionin T-cells are Janus kinases (JAK) such as JAK1, JAK2, JAK3 and TYK2,IL-2 inducible T-cell kinases (ITK), and TEC family of kinases such asresting lymphocyte kinases (RLK).

Janus kinases involving JAK3 have been widely investigated as a targetfor autoimmune and/or inflammatory diseases. Among them, unlike JAK2involved in hematosis and erythrocyte homeostasis or JAK1 expressed invarious tissues, JAK3 is expressed in lymphocytes and plays a veryimportant role in signal transduction via various cytokines, i.e., IL-2,IL-4, IL-7, IL-9 and IL-15, which is more attractive (Flanagan et al,Journal of medicinal Chemistry, 53, 8468, 2010). According to animalstudies, JAK3 plays a role in the maturation of B-cells and T-cells aswell as in maintaining T-cell functions.

Therefore, JAK3 inhibitors may be useful in the treatment of rheumatoidarthritis, psoriasis, atopic dermatitis, lupus, multiple sclerosis, TypeI diabetes and complications from diabetes, cancer, asthma, autoimmunethyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer'sdisease, leukemia, and other indications where immunosuppression wouldbe desirable, such as organ transplants or xeno transplantation (Pesu M,Laurence A, Kishore N, et al., Immunol Rev 223, 132, 2008.; Kawahara A,Minami Y, Miyazaki T, et al., Proc Natl Acad Sci USA 92, 8724, 1995;Nosaka T, van Deursen J M A, Tripp R A, et al., Science 270, 800, 1995;Papageorgiou Ac, Wikman L E K., et al., Trends Pharm Sci 25, 558, 2004).

Meanwhile, other TEC family of kinases also play an important role inT-cell activation (Pamela L. Schwartzberg, et al., Nature ReviewsImmunology 5, 284, 2005). For example, deletion of ITK which ischaracteristically expressed in T-cells in mice led to decreased cellproliferation which is induced by stimulation via T-cell receptors anddecreased secretion of various cytokines such as IL-2, IL-4, IL-5, IL-10and IFN-γ (Schaeffer et al., Science 284, 638, 1999; Fowell et al.,Immunity 11, 399, 1999; Schaffer et al., Nature Immunology 2, 1183,2001).

In addition, in ITK-deficient mice, immune symptoms of allergic asthmawere attenuated and lung inflammation, eosinophil infiltration, andmucous production in response to challenge with the allergen ovalbuminwere drastically reduced (Muller et al., Journal of Immunology 170,5056, 2003). This shows that ITK inhibitors would be useful in thetreatment of asthma.

Further, ITK has also been implicated in atopic dermatitis. This genehas been reported to be more highly expressed in peripheral bloodT-cells from patients with severe atopic dermatitis, compared withcontrols or patients with mild atopic dermatitis (Matsumoto et al.,International archives of Allergy and Immunology 129, 327, 2002).

Meanwhile, RLK functions to activate the secretion of IL-2 which isproduced by signal transduction of T-cell receptors of splenocytes.Thus, the inhibition of RLK may reduce various responses by T-cells(Schaeffer et al., Nature Immunology 2, 1183, 2001; Schaeffer et al.,Science 284, 638, 1999).

In addition, bone marrow tyrosine kinase (BMX) has been known to beinvolved in epithelial and endothelial cell migration (Pan et al., Mol.Cell. Biol. 2002, 22, 7512). Therefore, BMK inhibitors may be developedas anticancer agents for inhibiting the metastasis of cancer cells andangiogenesis.

As above, since TEC family kinases such as BTK, ITK, RLK, BMX and othersand Janus kinases such as JAK3 play a critical role in the activation ofB-cells and/or T-cells which is implicated in the pathogenesis ofinflammatory diseases, autoimmune diseases, and immunologically mediateddiseases, a compound for effectively inhibiting the kinases may beuseful as a therapeutic agent for various inflammatory diseases,autoimmune diseases, and immunity mediated diseases.

Furthermore, a compound for inhibiting BTK involved in B-cell activationinducing B-cell lymphoma, and BMX involved in metastasis of cancer cellsmay be useful as an anticancer or antitumor agent.

Therefore, the development of a compound, which can inhibit abovekinases and selectively inhibit variant EGFRs such as secondary T790Mmutations as well as L858R point mutation at exon 21 or in-framedeletion at exon 19, is one of very important challenges.

Even though it was suggested that EGFR irreversible inhibitors, whichform a covalent bond with Cystein773 (Cys773) positioned at an ATPdomain of EGFR, may show inhibitory effects on the activities of TECfamily of kinases such as BTK, ITK, RLK and BMX in which cysteine ispresent in a same position of the amino acid sequence, as well askinases such as JAK3 or BLK (Wooyoung Hur, et al., Bioorg. Med. Chem.Lett. 18, 5916, 2008), there has been no developed for a compound whichcan inhibit irreversibly, selectively and effectively variant EGFR, BTK,JAK3, ITK, RLK, BMX and/or BLK.

SUMMARY OF THE INVENTION

Therefore, it is an object of the present invention to provide a novelfused pyrimidine derivative which selectively and effectively inhibitscancers or tumors induced by an epidermal growth factor receptor (EGFR)tyrosine kinase or a mutant thereof with reduced adverse side effects.

It is another object of the present invention to provide a novel fusedpyrimidine derivative which can treat cancers, tumors, inflammatorydiseases, autoimmune diseases, or immunologically mediated diseasesmediated by abnormally activated B-lymphocytes, T-lymphocytes or both,by repressing non-receptor tyrosine kinases such as TEC family kinases(e.g. BTK, ITK, BMX or RLK) and janus kinases (e.g. JAK3).

It is still another object of the present invention to provide apharmaceutical composition for preventing or treating cancers, tumors,inflammatory diseases, autoimmune diseases, or immunologically mediateddiseases which comprises said novel fused pyrimidine derivative.

In accordance with one aspect of the present invention, there isprovided a compound of formula (I) or a pharmaceutically acceptable saltthereof:

wherein,

W is O or S;

X is O, NH, S, SO or SO₂;

Y is hydrogen atom, halogen atom, C₁₋₆alkyl or C₁₋₆alkoxy;

A and B are each independently hydrogen atom, halogen atom, ordi(C₁₋₆alkyl)aminomethyl;

Z is aryl or heteroaryl having one or more substituents selected fromthe group consisting of: hydrogen atom, halogen atom, hydroxy, nitro,cyano, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl,di(C₁₋₆alkyl)aminoC₂₋₆alkoxycarbonyl, amino, C₁₋₆alkylamino,di(C₁₋₆alkyl)amino, carbamoyl, C₁₋₆alkylcarbamoyl,di(C₁₋₆alkyl)carbamoyl, di(C₁₋₆alkyl)aminoC₂₋₆alkylcarbamoyl, sulfamoyl,C₁₋₆alkylsulfamoyl, di(C₁₋₆alkyl)sulfamoyl,di(C₁₋₆alkyl)aminoC₂₋₆alkylsulfamoyl, C₁₋₆alkylsulfonyl,C₁₋₆alkylsulfinyl, di(C₁₋₆alkyl)phosphonyl, hydroxyC₁₋₆alkyl,hydroxycarbonylC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl,C₁₋₆alkylsulfonylC₁₋₆alkyl, C₁₋₆alkylsulfinylC₁₋₆alkyl,di(C₁₋₆alkyl)phosphonylC₁₋₆alkyl, hydroxyC₂₋₆alkoxy,C₁₋₆alkoxyC₂₋₆alkoxy, aminoC₁₋₆alkyl, C₁₋₆alkylaminoC₁₋₆alkyl,di(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoacetyl, aminoC₂₋₆alkoxy,C₁₋₆alkylaminoC₂₋₆alkoxy, di(C₁₋₆alkyl)aminoC₂₋₆alkoxy,hydroxyC₂₋₆alkylamino, C₁₋₆alkoxyC₂₋₆alkylamino, aminoC₂₋₆alkylamino,C₁₋₆alkylaminoC₂₋₆alkylamino, di(C₁₋₆alkyl)aminoC₂₋₆alkylamino,heteroaryl, heterocycle, heterocyclic oxy, heterocyclic thio,heterocyclic sulfinyl, heterocyclic sulfonyl, heterocyclic sulfamoyl,heterocyclic C₁₋₆alkyl, heterocyclic C₁₋₆alkoxy, heterocyclic amino,heterocyclic C₁₋₆alkylamino, heterocyclic aminoC₁₋₆alkyl, heterocycliccarbonyl, heterocyclic C₁₋₆alkylcarbonyl, heterocycliccarbonylC₁₋₆alkyl, heterocyclic C₁₋₆alkylthio, heterocyclicC₁₋₆alkylsulfinyl, heterocyclic C₁₋₆alkylsulfonyl, heterocyclicaminocarbonyl, heterocyclic C₁₋₆alkylaminocarbonyl, heterocyclicaminocarbonylC₁₋₆alkyl, heterocyclic carboxamido, and heterocyclicC₁₋₆alkylcarboxamido;

the aryl refers to a C₆₋₁₂ cyclic or bicyclic aromatic ring;

the heteroaryls each independently refer to a 5- to 12-membered cyclicor bicyclic aromatic hetero ring having one or more N, O or S;

the heterocycles each independently refer to a saturated or partiallyunsaturated 3- to 12-membered cyclic or bicyclic hetero ring having oneor more N, O, S, SO or SO₂, in which a carbon atom forming theheterocycle optionally has one or more substituents selected from thegroup consisting of C₁₋₆alkyl, hydroxy, hydroxyC₁₋₆alkyl,hydroxycarbonyl, C₁₋₆alkoxy, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino,di(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminocarbonyl, heterocycle,heterocyclic C₁₋₆alkyl, and heteroaryl, and in which, provided that theheterocycle optionally comprises a nitrogen atom, the nitrogen atomoptionally has a substituent selected from the group consisting ofhydrogen atom, C₁₋₆alkyl, monohalogenoC₁₋₆alkyl, dihalogenoC₁₋₆alkyl,trihalogenoC₁₋₆alkyl, C₃₋₆cycloalkyl, hydroxyC₂₋₆alkyl,C₁₋₆alkoxyC₂₋₆alkyl, C₁₋₆alkylcarbonyl, hydroxyC₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl, carbamoyl, C₁₋₆alkylcarbamoyl,di(C₁₋₆alkyl)carbamoyl, sulfamoyl, C₁₋₆alkylsulfamoyl,di(C₁₋₆alkyl)sulfamoyl, C₁₋₆alkylsulfonyl, aminoC₂₋₆alkyl,C₁₋₆alkylaminoC₂₋₆alkyl, di(C₁₋₆alkyl)aminoC₂₋₆alkyl,di(C₁₋₆alkyl)aminoC₁₋₆alkylcarbonyl, heterocycle, heterocyclic oxy,heterocyclic thio, heterocyclic sulfinyl, heterocyclic sulfonyl,heterocyclic C₁₋₆alkyl, heterocyclic carbonyl, heterocyclicC₁₋₆alkylcarbonyl, heterocyclic C₁₋₆alkylsulfinyl, and heterocyclicC₁₋₆alkylsulfonyl (wherein, when the nitrogen atom forms tertiary amine,it is optionally of an N-oxide form); and

optionally, the C₁₋₆alkyl is partially unsaturated or has aC₃₋₆cycloalkyl moiety, and a carbon atom in the heterocycle exists in acarbonyl form.

In accordance with another aspect of the present invention, there isprovided a pharmaceutical composition for preventing or treatingcancers, tumors, inflammatory diseases, autoimmune diseases, orimmunologically mediated diseases which comprises the compound offormula (I) or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other objects and features of the present invention willbecome apparent from the following description of the invention, whentaken in conjunction with the accompanying drawings, which respectivelyshow:

FIG. 1: size change of tumors by oral administration of the compoundobtained in Example 2 in nude mice xenografted with NCI-H1975 cancercells;

FIG. 2: body-weight change by oral administration of the compoundobtained in Example 2 in nude mice xenografted with NCI-H1975 cancercells; and

FIG. 3: change in an arthritis clinical score by oral administration ofthe compound obtained in Example 1 in a collagen-induced arthritis (CIA)model.

DETAILED DESCRIPTION OF THE INVENTION

In the compound of formula (I), preferred examples of Z includesubstituents selected from the group consisting of formulae Z1 to Z203,but are not limited thereto:

More preferred examples of the compound of formula (I) according to thepresent invention are as follows:

-   N-(3-(2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(4-tert-butyl-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(4-(2-fluoro-ethyl)-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(4-(2-methoxy-ethyl)-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(4-(2-hydroxy-ethyl)-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(4-hydroxy-4-methyl-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(3,4,5-trimethyl-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(2-methoxy-4-(1-methyl-piperidin-4-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(2-methoxy-4-(1-methyl-piperidin-3-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(3-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   Diethyl(4-((4-(3-acrylamidophenoxy)thieno[3,2-d]pyrimidin-2-yl)amino)phenyephosphonate;-   N-(3-(2-(4-[1,4]bipiperidinyl-1′-yl-3-fluoro-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-((2-((3-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-(2-(4-(1-methylpiperidin-4-ylamino)-3-chlorophenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(2-fluoro-4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(3-methyl-4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   4-((4-(3-acrylamidophenoxy)thieno[3,2-d]pyrimidin-2-yl)amino)-2-methyl-N-(1-methylpiperidin-4-yl)benzamide;-   N-(4-methyl-3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(4-fluoro-3-(2-(4-(4-methyl-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(4-methoxy-3-(2-(4-(4-methylpiperazin-1-yl)-phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(5-(4-methylpiperazin-1-yl)pyridin-2-ylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   4-methyl-piperazin-1-carboxylic acid    (4-(4-(3-acryloylamino-phenoxy)-thieno[3,2-d]pyrimidin-2-ylamino)-phenyl)-amide;-   N-(4-((4-(3-acrylamidophenoxy)thieno[3,2-d]pyrimidin-2-yl)amino)-2-fluorophenyl)-4-methylpiperazin-1-carboxamide;-   N-(3-(2-(4-(4-ethylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(4-isopropyl-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(4-(2,2-difluoro-ethyl)-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-imidazol-1-yl-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(piperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(4-(2-dimethylamino-acetyl)-piperazin-1-yl)-3-fluoro-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(3-chloro-4-(piperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(4-(methylsulfonyl)piperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(4-(morpholin-4-carbonyl)-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(1,4-dimethyl-3-oxo-piperazin-2-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-morpholinophenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-((2-((4-((2-(dimethylamino)ethyl)amino)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-((2-(4-methylpiperazin-1-yl)ethyl)amino)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-(2-(4-thiomorpholinophenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(1-oxo-1λ⁴-thiomorpholin-4-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   (S)—N-(3-(2-(4-(3-(dimethylamino)pyrrolidin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(4-pyrrolidin-1-yl-piperidin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-[1,4′]bipiperidinyl-1′-yl-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   1-(4-(4-(3-acryloylamino-phenoxy)-thieno[3,2-d]pyrimidin-2-ylamino)-phenyl)-piperidin-4-carboxylic    acid dimethylamide;-   N-(3-(2-(4-(dimethylamino)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(2-hydroxy-ethyl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(2-dimethylamino-ethyl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(3-chloro-4-fluorophenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-hydroxyphenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-((2-((4-acetylphenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-(1,4,5,6-tetrahydropyrimidin-2-yl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxo)phenyl)acrylamide;-   N-(3-(2-(3-fluoro-2-methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(3R-imidazol-1-yl-pyrrolidin-1-yl)-phenylamino]-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(3-imidazol-1-yl-pyrrolidin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(4-imidazol-1-yl-piperidin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(4-dimethylamino-piperidin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(4-morpholin-4-yl-piperidin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(3-fluoro-4-(4-pyrrolidin-1-yl-piperidin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(3-fluoro-4-(4-morpholin-4-yl-piperidin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(3-chloro-4-(4-pyrrolidin-1-yl-piperidin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(3-chloro-4-(4-morpholin-4-yl-piperidin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(4-hydroxypiperidin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-((2-((4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-(2-(4-(4-(ethylsulfonyl)piperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-((4-ethylpiperazin-1-yl)methyl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-diethylaminomethyl-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(4-morpholin-4-yl-piperidin-1-ylmethyl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   (E)-N-(3-((2-((4-(3-(dimethylamino)prop-1-en-1-yl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-((1-methylpiperidin-4-yl)amino)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-(2-(4-diethylaminomethyl-2-methoxy-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-((4-methylpiperazin-1-yl)methyl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(3-fluoro-4-(4-methyl-piperazin-1-ylmethyl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(piperidin-1-ylmethyl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-azetidin-1-ylmethyl-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-pyrrolidin-1-ylmethyl-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(morpholinomethyl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-((2-((4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-((4-hydroxypiperidin-1-yl)methyl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-((4-(dimethylamino)piperidin-1-yl)methyl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   Dimethyl(4-((4-(3-acrylamidophenoxy)thieno[3,2-d]pyrimidin-2-yl)amino)benzylphosphonate;-   N-(3-(2-(4-((dimethylamino)methyl)-3-fluorophenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-3-fluorophenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-((4-(dimethylamino)piperidin-1-yl)methyl)-3-fluorophenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-((1-methylpiperidin-4-ylamino)methyl)-3-fluorophenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-dimethylaminomethyl-2-methyl-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-((4-(cyclopropylmethyl)piperazin-1-yl)methyl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-((4-(1-methylpiperidin-4-yl)piperazin-1-yl)methyl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-methanesulfonylmethyl-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(2-methanesulfonyl-ethyl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(3-chloro-4-(4-(1-methyl-piperidin-4-yl)piperazin-1-ylmethyl)phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(4-cyclohexyl-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(5-(4-(2-hydroxy-ethyl)-piperazin-1-yl)-piridin-2-ylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(1-(4-ethylpiperazin-1-yl)ethyl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(4-ethylpiperazin-1-carbonyl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(4-(2-hydroxy-acetyl)-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(4-(2-dimethylamino-acetyl)-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   2-(4-((4-(3-acrylamidophenoxy)thieno[3,2-d]pyrimidin-2-yl)amino)phenyl)acetic    acid;-   N-(3-((2-((4-(methylsulfinyl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-(methylsulfonyl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   4-((4-(3-acrylamidophenoxy)thieno[3,2-d]pyrimidin-2-yl)amino)-N-methylbenzamide;-   4-((4-(3-acrylamidophenoxy)thieno[3,2-d]pyrimidin-2-yl)amino)-N,N-dimethylbenzamide;-   N-(3-((2-((4-(morpholin-4-carbonyl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-(4-methylpiperazin-1-carbonyl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-(2-(4-(4-(1-methyl-piperidin-4-yl)-piperazin-1-carbonyl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(4-hydroxy-piperidin-1-carbonyl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(3-methylamino-pyrrolidin-1-carbonyl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(3-dimethylamino-pyrrolidin-1-carbonyl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   4-(4-(3-acryloylamino-phenoxy)-thieno[3,2-d]pyrimidin-2-ylamino)-N-(2-dimethylamino-ethyl)-benzamide;-   N-(3-(2-(3-chloro-4-(4-ethylpiperazin-1-carbonyl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-((2-((3-chloro-4-((2-(dimethylamino)ethyl)amino)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   4-(4-(3-acryloylamino-phenoxy)-thieno[3,2-d]pyrimidin-2-ylamino)-2-chloro-N,N-dimethyl-benzamide;-   N-(3-(2-(3-chloro-4-(4-ethanesulfonyl-piperazin-1-carbonyl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   4-((4-(3-acrylamidophenoxy)thieno[3,2-d]pyrimidin-2-yl)amino-2-chloro-N-(1-methylpiperidin-4-yl)benzamide;-   N-(3-(2-(4-(4-ethylpiperazin-1-ylsulfonyl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-((2-((4-((methylsulfinyl)methyl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-(2-(methylsulfinyl)ethyl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-sulfamoylphenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-(morpholinosulfonyl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-(N-cyclopropylsulfamoyl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-(N-(2-(dimethylamino)ethyl)sulfamoyl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-(N-(1-methylpiperidin-4-yl)sulfamoyl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-(N-(1-isopropylpiperidin-4-yl)sulfamoyl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   3-(dimethylamino)propyl-4-((4-(3-acrylamidophenoxy)thieno[3,2-d]pyrimidin-2-yl)amino)benzoate;-   N-(3-(2-(4-(2-(4-ethylpiperazin-1-yl)ethyl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(2-piperidin-1-yl-ethyl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(2-(4-ethylpiperazin-1-yl)acetyl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(1-ethylpiperidin-4-yloxy)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(3-fluoro-4-(1-methyl-piperidin-4-yloxy)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(2-morpholinoethoxy)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(2-methoxy-ethoxy)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-((2-((4-(2-(dimethylamino)ethoxy)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-(2-(diethylamino)ethoxy)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-(2-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(3-fluoro-4-(2-methoxy-ethoxy)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(2-dimethylamino-ethoxy)-3-fluoro-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(2-diethylamino-ethoxy)-3-fluoro-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(3-fluoro-4-(2-(4-methyl-piperazin-1-yl)-ethoxy)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(3-methoxy-4-(2-morpholin-4-yl-ethoxy)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   (E)-4-(dimethylamino)-N-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)but-2-enamide;-   N-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)phenyl)acrylamide;-   N-(3-(2-(4-(4-ethyl-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide;-   N-(3-(2-(4-(4-isopropyl-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide;-   N-(3-(2-(4-(1-methyl-piperidin-4-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide;-   N-(3-(2-(4-(1-methyl-piperidin-3-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide;-   N-(3-(2-(4-dimethylaminomethyl-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide;-   N-(3-(2-(4-piperidin-1-ylmethyl-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide;-   N-(3-(2-(4-(2-dimethylamino-ethyl)-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide;-   N-(3-((2-((4-(2-(4-methylpiperazin-1-yl)ethyl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acrylamide;-   N-(3-(2-(4-(2-dimethylamino-ethoxy)-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide;-   N-(3-(2-(4-(3-dimethylamino-propoxy)-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide;-   N-(3-(2-(3-fluoro-4-(4-methyl-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide;-   N-(3-(2-(3-fluoro-4-(1-methyl-piperidin-4-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide;-   N-(3-(2-(3-fluoro-4-(1-methyl-piperidin-4-ylamino)-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide;-   N-(3-(2-(2-methoxy-4-piperidin-1-ylmethyl-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide;-   N-(4-fluoro-3-(2-(4-(4-methyl-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide;-   N-(4-fluoro-3-(2-(3-fluoro-4-(4-methyl-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide;-   N-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylthio)phenyl)acrylamide;-   N-(3-(2-(3-fluoro-4-(1-methyl-piperidin-4-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-ylsulfanyl)-phenyl)-acrylamide;-   N-(3-(2-(3-fluoro-4-morpholin-4-yl-phenylamino)-thieno[3,2-d]pyrimidin-4-ylsulfanyl)-phenyl)-acrylamide;-   (E)-4-(dimethylamino)-N-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylthio)phenyl)but-2-enamide;-   N-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylsulfinyl)phenyl)acrylamide;-   (Z)-3-chloro-N-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   (E)-3-chloro-N-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(4-ethylpiperazin-1-yl)-2-methoxyphenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(2-methoxy-4-morpholinophenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   4-((4-(3-acrylamidophenoxy)thieno[3,2-d]pyrimidin-2-yl)amino)-2-methoxy-N-(1-methylpiperidin-4-yl)benzamide;-   N-(3-(2-(4-(piperidin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(pyrrolidin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   1-(4-((4-(3-acrylamidophenoxy)thieno[3,2-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-carboxylic    acid;-   N-(3-(2-(4-(4-dimethylaminomethyl-piperidin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(4-piperidin-1-ylmethyl-piperidin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(1-methyl-1,2,3,6-tetrahydro-piridin-4-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(1-methyl-piperidin-4-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(1-ethyl-piperidin-4-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(1-isopropyl-piperidin-4-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(1-methyl-piperidin-3-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-dimethylaminomethyl-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(3-chloro-4-(1-methyl-piperidin-4-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   4-(4-(3-acrylamidophenoxy)thieno[3,2-d]pyrimidin-2-ylamino)-N-(2-(pyrrolidin-1-yl)ethyl)benzamide;-   N-(3-((2-((4-(2-((1-methylpiperidin-4-yl)amino)-2-oxoethyl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-(2-(4-(3-piperidin-1-yl-propenyl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(4-(3-pyrrolidin-1-yl-propionylamino)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   4-((4-(3-acrylamidophenoxy)thieno[3,2-d]pyrimidin-2-yl)amino-N-(tetrahydro-2H-pyran-4-yl)benzamide;-   4-((4-(3-acrylamidophenoxy)thieno[3,2-d]pyrimidin-2-yl)amino-N-(1-methylpiperidin-4-yl)benzamide;-   4-((4-(3-acrylamidophenoxy)thieno[3,2-d]pyrimidin-2-yl)amino)-N-(1-isopropylpiperidin-4-yl)benzamide;-   4-(4-(3-acryloylamino-phenoxy)-thieno[3,2-d]pyrimidin-2-ylamino)-3-methoxy-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;-   N-(3-(2-(4-(4-(N,N-dimethylsulfamoyl)piperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(2-(4-(ethylsulfonyl)piperazin-1-yl)ethyl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(6-(4-methylpiperazin-1-yl)pyridin-3-ylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-((2-(piridin-3-ylamino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((6-morpholinopiridin-3-yl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((6-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)pyridin-3-yl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((6-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)pyridin-3-yl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((6-(4-(dimethylamino)piperidin-1-yl)pyridin-3-yl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((6-([1,4′-bipiperidin]-1′-yl)pyridin-3-yl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((6-((2-(piperidin-1-yl)ethyl)amino)pyridin-3-yl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((6-((1-isopropylpiperidin-4-yl)amino)pyridin-3-yl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((6-(methylsulfinyl)pyridin-3-yl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-(2-(3-fluoro-4-morpholinophenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-((2-((3-fluoro-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((3-fluoro-4-((1-isopropylpiperidin-4-yl)amino)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-(2-(3-fluoro-4-(4-(methylsulfonyl)piperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(4-(4-(ethanesulfonylpiperazin-1-yl)-3-fluoro-phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)acrylamide;-   N-(3-(2-(4-(2,6-cis-dimethylmorpholino)-3-fluorophenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide;-   N-(3-(2-(3-fluoro-4-(1-methyl-piperidin-4-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(3-fluoro-4-(1-methyl-piperidin-3-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(3-fluoro-4-(2-morpholin-4-yl-ethoxy)phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-((2-((4-((2-(dimethylamino)ethyl)amino)-3-fluorophenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-((2-(dimethylamino)ethyl)amino)-3,5-difluorophenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((3,5-difluoro-4-((1-methylpiperidin-4-yl)amino)phenyl)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-(2-(4-(1-amino-cyclopropyl)-phenylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-[1-(2-dimethylamino-acetyl)-2,3-dihydro-1H-indol-5-ylamino]-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-(2-(1-methyl-1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;-   N-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)furo[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)furo[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-morpholinophenyl)amino)furo[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-((dimethylamino)methyl)phenyl)amino)furo[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-((4-(dimethylamino)piperidin-1-yl)methyl)phenyl)amino)furo[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((3-fluoro-4-(1-methylpiperazin-4-yl)phenyl)amino)furo[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((4-(2-dimethylamino)ethyl)amino)-3-fluorophenyl)amino)furo[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-((2-((3-fluoro-4-((1-methylpiperidin-4-yl)amino)phenyl)amino)furo[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;-   N-(3-(2-(3-methoxy-4-(4-methyl-piperazin-1-yl)-phenylamino)-furo[3,2-d]pyrimidin-4-yloxy)-phenyl)-acrylamide;    and-   N-(3-((2-((4-sulfamoylphenyl)amino)furo[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide.

The compound of formula (I) according to the present invention may beprepared by the procedure shown in Reaction Scheme (I):

wherein,

A, B, W, X, Y and Z have the same meanings as defined above;

R is hydrogen, methyl, or ethyl; and

N′ is nitro, or amine protected with tert-butyloxycarbonyl (Boc).

As shown in Reaction Scheme (I), a compound of formula (VIII) issubjected to a condensation reaction with urea in an organic solvent(e.g., N,N-dimethylformamide, N,N-dimethylacetamide orN-methylpyrrolidone) at a temperature ranging from reflux temperature to200° C.; or with potassium cyanate under an acidic condition such as 6%to 50% of aqueous acetic acid at a temperature ranging from roomtemperature to 100° C., to obtain a condensed compound of formula (VII).

The compound of formula (VII) thus obtained is refluxed with stirring inthe presence of a chlorinating agent (e.g., phosphorus oxychloride orthionyl chloride) to obtain a chlorinated compound of formula (VI),followed by a reaction in an organic solvent (e.g., dimethylsulfoxide,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone,acetonitrile, tetrahydrofuran, 1,4-dioxane, toluene or benzene) in thepresence of an inorganic base (e.g., cesium carbonate, sodium carbonateor potassium carbonate) at a temperature ranging from room temperatureto 100° C., inducing the substitution at the C-4 position of thecompound of formula (VI) with aniline, phenol or thiophenol derivativeof formula (V), to obtain a compound of formula (IV).

The compound of formula (IV) is reacted with Z—NH₂ in an alcoholsolution (e.g., 2-propanol or 2-butanol) in the presence of an inorganicacid (e.g., hydrochloric acid) or organic acid (e.g., trifluoroaceticacid) at a temperature ranging from 70° C. to reflux temperature; orwith Z—NH₂ in an organic solvent (e.g., 1,4-dioxane) in the presence ofa palladium catalyst (e.g., palladium (II) acetate ortris(dibenzylidenacetone)dipalladium(0), and in the presence of a ligand(e.g., bis(diphenylphosphino)(Xanthene)(Xantphos) or2,2′-bis(disphenylphosphino)-1,1′-binaphthyl (BINAP)) and an inorganicbase (e.g., cesium carbonate or sodium t-butoxide) at a temperature ofabout 100° C., to obtain a compound of formula (III) having a Z—NH₂group.

The compound of formula (III) in which N′ is nitro group is subjected toa hydrogenation using a palladium/carbon catalyst, or a reductionreaction mediated with Fe, to obtain an aniline compound of formula (II)whose a nitro group is substituted with an amino group. The compound offormula (III) in which N′ is amine group protected withtert-butyloxycarbonyl (Boc) is subjected to a reaction with an acid(e.g., trifluoroacetic acid or hydrochloric acid) in an organic solvent(e.g., methylene chloride), to obtain a deprotected aniline compound offormula (II).

Subsequently, the aniline compound of formula (II) is subjected to areaction with an acryloyl chloride substituted with A and B, in anorganic solvent (e.g., methylene chloride or tetrohydrofuran) or a mixedsolvent such as 50% aqueous tetrohydrofuran in the presence of aninorganic base (e.g., sodium bicarbonate) or organic base (e.g.,triethylamine or diisopropylethylamine) at a low temperature rangingfrom −10° C. to 10° C.; or with acrylic acid substituted with A and B,in pyridine using a coupling agent (e.g.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) or2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methaneaminium (HATU)), to obtain the inventive compound offormula (I) having an acrylamide group.

The compound of formula (I) of the present invention may also beprepared in the form of a pharmaceutically acceptable salt formed withan inorganic or organic acid such as hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolicacid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaricacid, fumaric acid, malic acid, mandelic acid, tartaric acid, citricacid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid,benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid,salicylic acid, methanesulfonic acid, benzenesulfonic acid andtoluenesulfonic acid.

The pharmaceutically acceptable salt of the present invention may beprepared by conventional methods, for example, by dissolving thecompound of formula (I) in a water-miscible organic solvent such asacetone, methanol, ethanol and acetonitrile, adding thereto an excessamount of an organic acid or an aqueous solution of inorganic acid, toinduce precipitation of salts from the resulting mixture, removing thesolvent and remaining free acid therefrom, and isolating theprecipitated salts.

The inventive compound of formula (I) or the pharmaceutically acceptablesalt thereof may include a hydrate and a solvate thereof.

Accordingly, the present invention provides a use of the inventivecompound for the manufacture of a medicament for preventing or treatingcancers, tumors, inflammatory diseases, autoimmune diseases, orimmunologically mediated diseases.

In addition, the present invention provides a pharmaceutical compositionfor preventing or treating cancers, tumors, inflammatory diseases,autoimmune diseases, or immunologically mediated diseases whichcomprises the inventive compound as an active ingredient.

Further, the present invention provides a method for preventing ortreating cancers, tumors, inflammatory diseases, autoimmune diseases, orimmunologically mediated diseases, which comprises administering theinventive compound to a mammal in need thereof.

The inventive compound of formula (I) or a pharmaceutically acceptablesalt thereof selectively and effectively inhibits the growth of cancercells induced by an epidermal growth factor receptor (EGFR) tyrosinekinase or a mutant thereof as well as the resistance against drugs.Accordingly, the present invention provides a pharmaceutical compositionfor preventing or treating cancers or tumors induced by an EGFR tyrosinekinase or a mutant thereof which comprises the compound of formula (I)or a pharmaceutically acceptable salt thereof as an active ingredient.

Representative examples of the cancers or tumors may include, but arenot limited to, liver cancer, hepatocellular carcinoma, thyroid cancer,colorectal cancer, testicular cancer, bone cancer, oral cancer, basalcell carcinoma, ovarian cancer, brain tumor, gallbladder carcinoma,biliary tract cancer, head and neck cancer, colorectal cancer, vesicalcarcinoma, tongue cancer, esophageal cancer, glioma, glioblastoma, renalcancer, malignant melanoma, gastric cancer, breast cancer, sarcoma,pharynx carcinoma, uterine cancer, cervical cancer, prostate cancer,rectal cancer, pancreatic cancer, lung cancer, skin cancer, and othersolid cancer.

The inventive compound of formula (I) or a pharmaceutically acceptablesalt thereof can provide enhanced anticancer effects when it isadministered in combination with another anticancer agent for treatingcancers or tumors.

Representative examples of the anticancer agent for treating cancers ortumors may include, but are not limited to, cell signal transductioninhibitors (e.g., imatinib, gefitinib, bortezomib, erlotinib, sorafenib,sunitinib, dasatinib, vorinostat, lapatinib, temsirolimus, nilotinib,everolimus, pazopanib, trastuzumab, bevacizumab, cetuximab, ranibizumab,pegaptanib, panitumumab and the like), mitosis inhibitors (e.g.,paclitaxel, vincristine, vinblastine and the like), alkylating agents(e.g., cisplatin, cyclophosphamide, chromabucil, carmustine and thelike), anti-metabolites (e.g., methotrexate, 5-FU and the like),intercalating anticancer agents, (e.g., actinomycin, anthracycline,bleomycin, mitomycin-C and the like), topoisomerase inhibitors (e.g.,irinotecan, topotecan, teniposide and the like), immunotherapic agents(e.g., interleukin, interferon and the like) and antihormonal agents(e.g., tamoxifen, raloxifene and the like), and at least one anticanceragent selected therefrom may be included in the inventive pharmaceuticalcomposition.

Further, the inventive compound of formula (I) or a pharmaceuticallyacceptable salt thereof selectively and effectively inhibits Bruton'styrosine kinase (BTK), janus kinase 3 (JAK3), interleukin-2 inducingT-cell kinase (ITK), resting lymphocyte kinase (RLK), and bone marrowtyrosine kinase (BMX), which are mainly expressed in abnormallyactivated B-lymphocytes and/or T-lymphocytes. Namely, the inventivecompound of formula (I) or a pharmaceutically acceptable salt thereofcan treat or prevent cancers, tumors, inflammatory diseases, autoimmunediseases or immunologically mediated diseases caused by the abnormallyactivated B-lymphocytes, T-lymphocytes or both. Therefore, the presentinvention also provides a pharmaceutical composition for treating orpreventing cancers, tumors, inflammatory diseases, autoimmune diseases,or immunologically mediated diseases which comprises the compound offormula (I) or a pharmaceutically acceptable salt thereof as an activeingredient.

Representative examples of the inflammatory diseases, autoimmunediseases and immunologically mediated diseases may include, but are notlimited to, arthritis, rheumatoid arthritis, spondyloarthropathy, goutyarthritis, osteoarthritis, juvenile arthritis, other arthriticcondition, lupus, systemic lupus erythematosus (SLE), skin-relateddisease, psoriasis, eczema, dermatitis, atopic dermatitis, pain,pulmonary disorder, lung inflammation, adult respiratory distresssyndrome (ARDS), pulmonary sarcoidosis, chronic pulmonary inflammatorydisease, chronic obstructive pulmonary disease (COPD), cardiovasculardisease, artherosclerosis, myocardial infarction, congestive heartfailure, cardiac reperfusion injury, inflammatory bowl disease, Crohn'sdisease, ulcerative colitis, irritable bowl syndrome, asthma, sjogrensyndrome, autoimmunity thyroid disease, urticaria (cnidosis), multiplesclerosis, scleroderma, organ transplantation rejection, heteroplasticgraft, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease,Alzheimer's disease, diabetic associated disease, inflammation, pelvicinflammatory disease, allergic rhinitis, allergic bronchitis, allergicsinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma,myeloma, acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL),acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hairy cellleukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma,myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN),diffuse large B-cell lymphoma, and follicular lymphoma.

The inventive compound of formula (I) or a pharmaceutically acceptablesalt thereof can provide enhanced therapeutic effects when it isadministered in combination with another therapeutic agent for treatinginflammatory diseases, autoimmune diseases, or immunologically mediateddiseases.

Representative examples of the therapeutic agent for treating theinflammatory diseases, autoimmune diseases, or immunologically mediateddiseases may include, but are not limited to, steroid drugs (e.g.,prednisone, prednisolone, methyl prednisolone, cortisone,hydroxycortisone, betametasone, dexametasone and the like),methotrexates, leflunomides, anti-TNFα agents (e.g., etanercept,infliximab, adalimunab and the like), calcineurin inhibitors (e.g.,tacrolimus, pimecrolimus and the like) and antihistaminic drugs (e.g.,diphenhydramine, hydroxyzine, loratadine, ebastine, ketotifen,cetirizine, levocetirizine, fexofenadine and the like), and at least onetherapeutic agent selected therefrom may be included in the inventivepharmaceutical composition.

The inventive compound of formula (I) or a pharmaceutically acceptablesalt thereof may be administered orally or parenterally as an activeingredient in an effective amount ranging from about 0.1 to 2,000 mg/kg,preferably 1 to 1,000 mg/kg body weight per a day in case of mammalsincluding human (of approximately 70 kg body weight) in a single to 4divided doses per a day, or on/off schedules. The dosage of the activeingredient may be adjusted in light of various relevant factors such asthe condition of the subject to be treated, type and seriousness ofillness, administration rate, and opinion of doctor. In certain cases,an amount less than the above dosage may be suitable. An amount greaterthan the above dosage may be used unless it causes deleterious sideeffects and such amount can be administered in divided doses per day.

The inventive pharmaceutical composition may be formulated in accordancewith any of the conventional methods in the form of tablet, granule,powder, capsule, syrup, emulsion or microemulsion for oraladministration, or for parenteral administration includingintramuscular, intravenous and subcutaneous routes.

The inventive pharmaceutical composition for oral administration may beprepared by mixing the active ingredient with a carrier such ascellulose, calcium silicate, corn starch, lactose, sucrose, dextrose,calcium phosphate, stearic acid, magnesium stearate, calcium stearate,gelatin, talc, surfactant, suspension agent, emulsifier and diluent.Examples of the carrier employed in the injectable composition of thepresent invention are water, a saline solution, a glucose solution, aglucose-like solution, alcohol, glycol, ether (e.g., polyethylene glycol400), oil, fatty acid, fatty acid ester, glyceride, a surfactant, asuspension agent and an emulsifier.

The present invention is further described and illustrated in examplesprovided below, which are, however, not intended to limit the scope ofthe present invention.

Example 1 Preparation ofN-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidine-4-yloxy)phenyl)acrylamide

Step 1) Preparation of thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

Methyl 3-aminothiophene-2-carboxylate (4.9 g, 31.3 mmol) and urea (19 g,187 mmol) were dissolved in N,N-dimethylformamide (10 mL), the reactiontemperature was raised to 190° C., followed by stirring for 12 hours.After the reaction was complete, the reaction mixture was added to 1NNaOH aqueous solution, cooled to room temperature and filtered under areduced pressure to remove the insoluble precipitate. The filtrate wasacidified (pH 2) with 2N HCl aqueous solution, and the resulting solidwas filtered under a reduced pressure with washing using distilledwater. The resulting solid was dried under a reduced pressure to obtainthe title compound (yield: 3.2 g, 61.5%).

¹H-NMR (300 MHz, CDCl₃) δ 11.59 (s, 1H), 11.14 (s, 1H), 8.00 (d, 1H),6.90 (d, 1H).

Step 2) Preparation of 2,4-dichlorothieno[3,2-d]pyrimidine

The compound (3.2 g, 19.4 mmol) obtained in Step 1 was dissolved inphosphorous oxychloride (12 mL) and refluxed with stirring for 3 hoursat 200° C. After the reaction was complete, the reaction mixture wascooled to room temperature and added dropwise to 4° C. distilled waterwith stirring vigorously. The resulting solid was filtered under areduced pressure with washing using distilled water, and the resultingsolid was dried under a reduced pressure to obtain the title compound(yield: 2.9 g, 73.3%).

¹H-NMR (300 MHz, DMSO-d₆) δ 8.74 (d, 1H), 7.78 (d, 1H).

Step 3) Preparation of2-chloro-4-(3-nitrophenoxy)thieno[3,2-d]pyrimidine

The compound (2.9 g, 14.2 mmol) obtained in Step 2 was dissolved inN,N-dimethylsulfoneamide (70 mL), and 3-nitrophenol (1.9 g, 14.2 mmol)and cesium carbonate (9.2 g, 28.4 mmol) were added thereto, followed bystirring room temperature for 1 hour. After the reaction was complete,distilled water was added to the reaction mixture, and the resultingsolid was filtered under a reduced pressure with washing with distilledwater. The resulting solid was dried under a reduced pressure to obtainthe title compound (yield: 4.0 g, 91.8%).

¹H-NMR (300 MHz, CDCl₃) δ 8.25-8.17 (m, 2H), 8.08 (s, 1H), 7.69-7.66 (m,2H), 7.57 (d, 1H).

Step 4) Preparation ofN-(4-(4-methylpiperazin-1-yl)phenyl)-4-(3-nitrophenoxy)thieno[3,2-d]pyrimidine-2-amine

The compound (12.9 mmol) obtained in Step 3 was dissolved in 2-butanol(70 mL), and 4-(4-methylpiperazin-1-yl)benzeneamine (12.9 mmol) andtrifluoroacetic acid (12.9 mmol) were added thereto. The mixture wasstirred at 100° C. for 16 hours to complete the reaction, diluted withdichloromethane, and then washed with sat. NaHCO₃ aqueous solution. Theorganic layer was dried with anhydrous sodium sulfate and then filteredand distilled under a reduced pressure. The residue was separated bycolumn chromatography (dichloromethane:methanol=20:1 (volume ratio)) toobtain the title compound (yield: 42%).

Step 5) Preparation of4-(3-aminophenoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)thieno[3,2-d]pyrimidine-2-amine

Iron (27.1 mmol) and 12 N HCl aqueous solution (2.17 mmol) were dilutedwith 50% ethanol aqueous solution (30 mL), followed by stirring at 100°C. for 10 min. The compound (5.42 mmol) obtained in Step 4 was dissolvedin 50% ethanol aqueous solution (30 mL) and then added to the reactionflask in which iron was activated, followed by stirring at 100° C. for 1hour. After the reaction was complete, the reaction mixture was filteredwith celite to remove iron, and the filtrate was distilled under areduced pressure. The residue was distilled with dichloromethane andwashed with sat. NaHCO₃ aqueous solution. The organic layer was driedwith anhydrous sodium sulfate and then filtered and distilled under areduced pressure. The residue was separated by column chromatography(dichloromethane:methanol=10:1 (volume ratio)) to obtain the titlecompound (yield: 67.8%).

Step 6) Preparation ofN-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidine-4-yloxy)phenyl)acrylamide

The compound (3.69 mmol) obtained in Step 5 and NaHCO₃ (11.07 mmol) weredistilled with tetrahydrofuran (40 mL) and distilled water (6 mL), andacryloyl chloride (3.69 mmol) was added thereto slowly at 0° C. withstirring for 15 min. After the reaction was complete, the reactionmixture was distilled with dichloromethane and then washed with sat.NaHCO₃ aqueous solution. The organic layer was dried with anhydroussodium sulfate and then filtered and distilled under a reduced pressure,and the residue was separated by column chromatography(chloroform:methanol=20:1 (volume ratio)) to obtain the title compound(yield: 68.2%).

¹H-NMR (300 MHz, CD₃OD) δ 8.03 (d, 1H), 7.67 (t, 1H), 7.63 (d, 1H), 7.43(t, 1H), 7.35 (d, 2H), 7.23 (d, 1H), 7.03 (m, 1H), 6.78 (d, 2H), 6.39(m, 2H), 5.77 (m, 1H), 3.08 (m, 4H), 2.59 (m, 4H), 2.33 (s, 3H);

MS (ESI⁺): m/z=487.4 [M+H]⁺.

The procedure of Example 1 was repeated except for using various aminederivatives represented by Z—NH₂ (Z is the same as defined above)instead of 4-(4-methylpiperazin-1-yl)benzeneamine in Step 4 to preparethe compounds of Examples 2 to 156 which are shown in Tables 1a to 1vbelow.

TABLE 1a Example Structure Analysis data 2

¹H-NMR (300 MHz, CDCl₃) δ 7.96 (m, 1H), 7.83 (d, 1H), 7.70 (d, 1H), 7.61(s, 1H), 7.45 (m, 2H), 7.25 (m, 2H), 7.01 (m, 1H), 6.45 (d, 1H),6.35-6.32 (m, 3H), 5.71 (dd, 1H); MS (ESI⁺): m/z = 517.1 [M + H]⁺. 3

¹H-NMR (300 MHz, CDCl₃) δ 7.83 (d, 1H), 7.70 (s, 1H), 7.45 (m, 1H), 7.42(m, 1H), 7.40 (m, 1H), 7.04 (m, 2H), 6.83 (dd, 1H), 6.80 (t, 1H), 6.43(dd, 1H), 6.27 (dd, 1H), 5.76 (dd, 1H), 3.03 (m, 4H), 2.60 (m, 4H), 2.36(s, 3H); MS (ESI⁺): m/z = 505.10 [M + H]⁺. 4

¹H-NMR (300 MHz, CDCl₃) δ 7.99 (m, 1H), 7.87 (m, 1H), 7.73 (s, 1H), 7.46(m, 2H), 7.29 (m, 1H), 7.00 (d, 1H), 6.79 (dd, 1H), 6.52 (t, 1H), 6.45(dd, 1H), 6.26 (dd, 1H), 5.78 (dd, 1H), 2.86 (m, 4H), 2.57 (m, 4H), 2.35(s, 3H); MS (ESI⁺): m/z = 505.10 [M + H]⁺. 5

¹H-NMR (300 MHz, DMSO-d₆) δ 10.35 (s, 1H), 9.75 (s, 1H), 8.33 (d, 1H),7.77 (m, 1H), 7.48 (m, 1H), 7.41 (m, 2H), 7.27 (m, 2H), 7.01 (m, H),6.43 (m, 1H), 6.21 (dd, 1H), 5.75 (dd, 1H), 2.97 (s, 4H), 2.37 (s, 4H),2.19 (s, 3H); MS (ESI⁺): m/z = 523.2 [M + H]⁺. 6

¹H-NMR (300 MHz, DMSO-d₆) δ 10.34 (s, NH), 8.28 (d, 1H), 8.21 (s, NH),7.71 (s, 1H), 7.56 (d, 1H), 7.45 (t, 1H), 7.40 (d, 1H), 7.29 (d, 1H),7.06 (d, 1H), 6.51 (t, 1H), 6.45 (m, 1H), 6.38 (d, 1H), 5.75 (d, 1H),3.76 (s, 3H), 2.90 (br, 4H), 2.44 (br, 4H), 2.21 (s, 3H); MS (ESI⁺): m/z= 535.0 [M + H]⁺. 7

¹H-NMR (300 MHz, DMSO-d₆) δ 10.33 (brs, 1H), 9.51 (brs, 1H), 8.30-8.28(m, 1H), 7.72-7.69 (m, 2H), 7.56 (m, 1H), 7.46- 7.41 (m, 2H), 7.36-7.34(m, 1H), 7.07-7.03 (m, 1H), 6.92-6.89 (m, 1H), 6.40-6.37 (m, 1H), 6.26(m, 1H), 5.77-5.76 (m, 1H), 2.77 (m, 4H), 2.42 (m, 4H), 2.20 (s, 3H); MS(ESI⁺): m/z = 521.1 [M + H]⁺. 8

¹H-NMR (300 MHz, CDCl₃) δ 7.82 (d, 1H), 7.58 (d, 1H), 7.43 (t, 1H), 7.36(d, 1H), 7.05 (dd, 1H), 6.80 (s, 1H), 6.77 (d, 2H), 6.45 (dd, 1H), 6.26(d, 1H), 5.65 (dd, 1H), 3.40 (m, 4H), 2.76 (m, 4H); MS (ESI⁺): m/z =501.13 [M + H]⁺.

TABLE 1b Example Structure Analysis data  9

¹H-NMR (300 MHz, CDCl₃) δ 7.83 (d, 1H), 7.70 (s, 1H), 7.45 (m, 1H), 7.42(m, 1H), 7.40 (m, 1H), 7.04 (m, 2H), 6.83 (dd, 1H), 6.80 (t, 1H), 6.43(dd, 1H), 6.27 (dd, 1H), 5.76 (dd, 1H), 3.03 (m, 4H), 2.60 (m, 4H), 2.36(s, 3H); MS (ESI⁺): m/z = 505.10 [M + H]⁺. 10

¹H-NMR (300 MHz, CDCl₃) δ 7.81-7.79 (m, 1H), 7.59-7.49 (m, 2H),7.42-7.37 (t, 1H), 7.29-7.26 (m, 2H), 7.05-7.02 (m, 1H), 6.90 (m, 1H),6.81-6.78 (m, 2H), 6.46-6.40 (m, 1H), 6.28- 6.24 (m, 1H), 5.78-5.75 (m,1H), 3.14-3.11 (m, 4H), 2.63-2.60 (m, 4H), 2.52-2.45 (q, 2H), 1.16-1.11(t, 3H); MS (ESI⁺): m/z = 501.2 [M + H]⁺. 11

¹H-NMR (300 MHz, CD₃OD) δ 8.04 (d, 1H), 7.66 (m, 2H), 7.43 (t, 1H), 7.33(d, 2H), 7.23 (d, 1H), 7.03 (m, 1H), 6.78 (d, 2H), 6.40 (m, 2H), 5.78(m, 1H), 3.08 (m, 4H), 2.65 (m, 5H). 1.14 (d, 6H); MS (ESI⁺): m/z =515.04 [M + H]⁺. 12

¹H-NMR (300 MHz, CDCl₃) δ 7.81-7.80 (d, 1H), 7.60-7.57 (m, 2H),7.44-7.32 (m, 4H), 7.06-7.03 (m, 1H), 6.83-6.78 (m, 3H), 6.47-6.41 (m,1H), 6.29-6.20 (m, 1H), 5.80-5.76 (m, 1H), 3.13- 3.10 (m, 4H), 2.76-2.73(m, 4H), 1.12 (s, 9H); (ESI⁺): m/z = 529 [M + H]⁺. 13

¹H-NMR (300 MHz, DMSO-d₆) δ; 10.35 (s, 1H), 9.21 (s, 2H), 8.24 (d, 1H),7.68 (m, 1H), 7.61 (d, 1H), 7.44 (d, 1H), 7.38 (m, 2H), 7.29 (d, 1H),7.03 (dd, 1H), 6.68 (d, 1H), 6.37 (dd, 1H), 6.27 (dd, 1H), 5.76 (dd,1H), 2.93 (m, 4H), 2.58 (m, 4H), 2.25 (m, 1H), 1.74 (m, 5H), 1.19 (m,5H); MS (ESI⁺): m/z = 555 [M + H]⁺. 14

¹H-NMR (300 MHz, CD₃OD) δ 8.08-8.06 (d, 1H), 7.69-7.68 (m, 2H),7.49-7.43 (t, 1H), 7.39-7.36 (d, 2H), 7.27-7.25 (d, 1H), 7.07 (m, 1H),6.83-6.80 (d, 2H), 6.45-6.40 (m, 2H), 5.82-5.78 (m, 1H), 4.73-4.70 (t,1H), 4.57-4.54 (t, 1H), 3.14-3.11 (m, 4H), 2.85-2.82 (t, 1H), 2.75-2.72(m, 5H). 15

¹H-NMR (300 MHz, DMSO-d₆) δ 10.3 (s, 1H), 9.21 (s, 1H), 8.24 (d, 1H),7.68 (m, 1H), 7.60 (d, 2H), 7.46 (s, 1H), 7.43 (m, 2H), 7.29 (d, 1H),7.04 (dd, 1H), 6.69 (d, 2H), 6.41 (dd, 1H), 6.27 (dd, 1H), 6.16 (t, 1H),5.75 (dd, 1H), 2.98 (m, 4H), 2.75 (t, 2H), 2.63 (m, 4H); MS (ESI⁺): m/z= 537.2 [M + H]⁺.

TABLE 1c Example Structure Analysis data 16

¹H-NMR (300 MHz, DMSO-d₆) δ 10.34 (brs, 1H), 9.22 (brs, 1H), 8.26-8.24(d, 1H), 7.67 (s, 1H), 7.62-7.60 (m, 1H), 7.46-7.39 (m, 3H), 7.31-7.29(d, 1H), 7.05-7.02 (m, 1H), 6.70-6.68 (m, 2H), 6.46- 6.37 (m, 1H),6.27-6.21 (m, 1H), 5.77-5.74 (m, 1H), 3.25-3.15 (q, 2H), 2.98 (m, 4H),2.71 (m, 4H); MS (ESI⁺): m/z = 554.97 [M + H]⁺. 17

¹H-NMR (300 MHz, CDCl₃) δ 7.81-7.79 (m, 1H), 7.55 (m, 2H), 7.42-7.32 (m,3H), 7.23 (m, 1H), 7.05-7.02 (m, 1H), 6.90 (brs, 1H), 6.80-6.77 (m, 2H),6.46-6.40 (m, 1H), 6.27-6.24 (m, 1H), 5.78-5.74 (m, 1H), 3.57-3.53 (t,2H), 3.37 (s, 3H), 3.14-3.10 (m, 4H), 2.67- 2.61 (m, 4H); MS (ESI⁺): m/z= 531.3 [M + H]⁺. 18

¹H-NMR (300 MHz, DMSO-d₆) δ 10.35 (brs, 1H), 9.22 (brs, 1H), 8.27-8.25(d, 1H), 7.70-7.69 (m, 1H), 7.64-7.61 (m, 1H), 7.48-7.40 (m, 2H),7.32-7.30 (m, 1H), 7.07-7.04 (m, 1H), 6.72-6.69 (m, 2H), 6.43-6.39 (m,1H), 6.29-6.24 (m, 1H), 5.80-5.76 (m, 1H), 4.43-4.39 (t, 1H), 3.56-3.50(q, 2H), 2.98 (m, 4H), 2.51 (m, 4H), 2.44-2.40 (t, 2H); MS (ESI⁺): m/z =517.2 [M + H]⁺. 19

¹H-NMR (300 MHz, DMSO-d₆) δ 10.33 (brs, 1H), 9.41 (brs, 1H), 8.26-8.24(m, 1H), 7.68-7.67 (m, 1H), 7.63-7.60 (m, 1H), 7.46-7.41 (m, 3H),7.31-7.29 (m, 1H), 7.06-7.03 (m, 1H), 6.74-6.71 (m, 2H), 6.41-6.38 (m,1H), 6.28-6.27 (m, 1H), 5.78-5.74 (m, 1H), 3.54-3.52 (m, 4H), 2.99-2.96(m, 2H), 2.93-2.89 (m, 2H), 2.01 (s, 3H); MS (ESI⁺): m/z = 515.3 [M +H]⁺. 20

¹H-NMR (300 MHz, DMSO-d₆) δ 10.45 (brs, 1H), 9.59 (brs, 1H), 8.31-8.30(m, 1H), 7.88 (s, 1H), 7.80-7.43 (m, 4H), 7.37 (d, 1H), 7.19-7.09 (m,3H), 6.51-6.43 (m, 1H), 6.29-6.23 (m, 1H), 5.79-5.76 (m, 1H), 4.10 (s,2H), 3.51-3.49 (m, 4H), 3.21-3.18 (m, 4H); MS (ESI⁺): m/z = 531.1 [M +H]⁺. 21

¹H-NMR (300 MHz, CDCl₃) δ 7.85 (d, 1H), 7.65-7.60 (m, 2H), 7.42- 7.35(m, 4H), 7.26 (d, 1H), 7.03-7.01 (m, 1H), 6.80.-6.87 (m, 2H), 6.41-6.41(m, 1H), 6.35-6.32 (m, 1H), 5.77-5.74 (m, 1H), 3.83-3.74 (m, 4H), 3.19(s, 2H), 3.15-3.06 (m, 4H), 2.32 (s, 6H); MS (ESI⁺): m/z = 558.2 [M +H]⁺. 22

¹H-NMR (300 MHz, DMSO-d₆) δ 10.38 (brs, 1H), 9.28 (brs, 1H), 8.31-8.26(m, 2H), 7.68-7.62 (m, 2H), 7.48-7.43 (m, 2H), 7.31 (d, 1H), 7.08 (d,1H), 6.74-6.71 (m, 2H), 6.49-6.40 (m, 1H), 6.29-6.23 (m, 1H), 5.79-5.76(m, 1H), 3.59-3.57 (m, 4H), 3.34-3.28 (m, 4H), 3.18-3.17 (m, 4H),3.05-2.97 (m, 4H); MS (ESI⁺): m/z = 586.2 [M + H]⁺.

TABLE 1d Example Structure Analysis data 23

¹H-NMR (300 MHz, DMSO-d₆) δ 10.34 (brs, 1H), 9.26 (brs, 1H), 8.27-8.25(m, 1H), 7.68 (s, 1H), 7.63-7.60 (m, 1H), 7.47- 7.42 (m, 3H), 7.32-7.30(m, 1H), 7.07-7.03 (m, 1H), 6.77-6.74 (m, 2H), 6.42-6.38 (m, 1H),6.28-6.22 (m, 2H), 5.79-5.75 (m, 1H), 3.22-3.20 (m, 4H), 3.10-3.08 (m,4H), 2.91 (s, 3H); MS (ESI⁺): m/z = 551.2 [M + H]⁺. 24

¹H-NMR (300 MHz, DMSO-d₆) δ 10.33 (brs, 1H), 9.25 (brs, 1H), 8.26-8.24(d, 1H), 7.68-7.67 (m, 1H), 7.62-7.59 (m, 1H), 7.47-7.41 (m, 3H),7.31-7.29 (d, 1H), 7.06-7.03 (m, 1H), 6.75- 6.72 (m, 2H), 6.43-6.38 (m,1H), 6.28-6.27 (m, 1H), 5.78-5.74 (m, 1H), 3.27-3.26 (m, 4H), 3.12-3.06(q, 2H), 3.06-3.03 (m, 4H), 1.24-1.29 (t, 3H); MS (ESI⁺): m/z = 565.09[M + H]⁺. 25

¹H-NMR (300 MHz, DMSO-d₆) δ 10.33 (brs, 1H), 9.26 (brs, 1H), 8.26-8.24(d, 1H), 7.68-7.67 (m, 1H), 7.63-7.60 (m, 1H), 7.46-7.41 (m, 3H),7.31-7.30 (d, 1H), 7.06-7.03 (m, 1H), 6.74- 6.71 (m, 2H), 6.41-6.38 (m,1H), 6.28-6.27 (m, 1H), 5.78-5.74 (m, 1H), 3.27-3.24 (m, 4H), 3.04-3.01(m, 4H), 2.78 (s, 6H); MS (ESI⁺): m/z = 580.08 [M + H]⁺. 26

¹H-NMR (300 MHz, CD₃OD) δ; 8.07 (d, 1H), 7.69 (m, 2H), 7.48 (t, 1H),7.38 (d, 2H), 7.27 (d, 1H), 7.06 (dd, 1H), 6.82 (d, 2H), 6.44-6.40 (m,2H), 5.82-5.78 (dd, 1H), 3.12 (m, 4H), 3.08 (m, 2H), 2.77 (m, 4H), 2.29(s, 1H), 2.09 (m, 3H), 1.98 (m, 2H), 1.64 (m, 2H) MS (ESI⁺): m/z = 570.3[M + H]⁺. 27

¹H-NMR (300 MHz, CDCl₃) δ 10.35 (s, NH), 9.35 (s, NH), 8.25 (d, 1H),7.68 (m, 2H), 7.41 (m, 3H), 7.30 (d, 1H), 7.04 (d, 1H), 6.71 (d, 2H),6.45 (dd, 1H), 6.24 (d, 1H), 5.76 (d, 1H), 3.38 (m, 2H), 2.30 (m, 4H),2.17 (s, 3H), 1.05 (s, 6H); MS (ESI⁺): m/z = 515.2 [M + H]⁺. 28

¹H-NMR (300 MHz, CDCl₃) δ 7.80-7.78 (d, 1H), 7.59 (m, 1H), 7.52 (m, 1H),7.44-7.22 (m, 3H), 7.06-7.03 (m, 1H), 6.74 (s, 1H), 6.55-6.41 (m, 3H),6.28-6.15 (m, 1H), 5.80-5.76 (m, 1H), 4.14 (s, 1H), 3.51-3.25 (m, 4H),2.94-2.91 (m, 1H), 2.63-2.60 (m, 1H), 2.35 (s, 3H), 1.98-1.80 (m, 3H),1.25-1.12 (m, 2H); MS (ESI⁺): m/z = 499 [M + H]⁺. 29

¹H-NMR (300 MHz, DMSO-d₆) δ 10.37 (s, 1H), 9.27 (s, 1H), 8.29 (d, 1H),7.71 (d, 1H), 7.64 (d, 1H), 7.48 (m, 2H), 7.34 (d, 1H), 7.08 (d, 1H),6.74 (m, 2H), 6.45 (m, 1H), 6.27 (d, 1H), 5.80 (d, 1H), 3.72 (m, 4H),2.98 (m, 4H); MS (ESI⁺): m/z = 474.4 [M + H]⁺.

TABLE 1e Example Structure Analysis data 30

¹H-NMR (300 MHz, CDCl₃) δ 7.82 (d, 1H), 7.58 (d, 1H), 7.43 (m, 1H), 7.36(d, 1H), 7.05 (dd, 1H), 6.80 (s, 2H), 6.77 (d, 2H), 6.45 (dd, 1H), 6.26(d, 1H), 5.65 (dd, 1H), 3.40 (m, 4H), 2.76 (m, 4H); MS (ESI⁺): m/z =490.05 [M + H]⁺. 31

¹H-NMR (300 MHz, DMSO-d₆) δ 8.04 (brs, 1H), 7.84-7.82 (d, 1H), 7.61-7.57(m, 2H), 7.43-7.37 (t, 1H), 7.36-7.33 (m, 2H), 7.25 (s, 1H), 7.05-7.02(m, 2H), 6.79-6.76 (m, 2H), 6.41 (m, 1H), 6.32-6.29 (m, 1H), 5.77-5.74(m, 1H), 3.88-3.79 (m, 2H), 3.42-3.34 (m, 2H), 2.91-2.81 (m, 4H); MS(ESI⁺): m/z = 506.00 [M + H]⁺. 32

¹H-NMR (300 MHz, CDCl₃) δ 7.86-7.84 (s, 1H), 7.60-7.53 (m, 3H),7.46-7.43 (m, 1H), 7.40-7.36 (m, 2H), 7.07-7.04 (m, 1H), 6.99 (s, 1H),6.79-6.76 (m, 2H), 6.48-6.43 (m, 1H), 6.30-6.21 (m, 1H), 5.82-5.78 (m,1H), 3.74 (m, 4H), 3.11-3.10 (m, 4H); MS (ESI⁺): m/z = 522.02 [M + H]⁺.33

¹H-NMR (300 MHz, DMSO-d₆) δ 10.34 (brs, 1H), 9.04 (s, 1H), 8.22 (d, 1H),7.69 (s, 1H), 7.61-7.55 (m, 1H), 7.45-7.26 (m, 4H), 7.08-7.03 (m, 1H),6.47-6.23 (m, 6H), 5.76 (d, 1H), 3.16-3.12 (m, 4H), 1.91 (m, 4H); MS(ESI⁺): m/z = 458.16 [M + H]⁺. 34

¹H-NMR (300 MHz, CDCl₃) δ 7.79 (d, 1H), 7.54 (m, 1H), 7.35 (m, 2H), 7.32(m, 2H), 7.25 (m, 1H), 7.23 (d, 1H), 6.75 (s, 1H), 6.46 (m, 1H), 6.25(m, 1H), 5.77 (d, 1H), 3.35 (m, 1H), 3.11 (t, 1H), 2.83 (m, 2H), 2.32(s, 6H), 2.18 (m, 1H), 1.72 (m, 1H); MS (ESI⁺): m/z = 501.4 [M + H]⁺. 35

¹H-NMR (300 MHz, DMSO-d₆) δ 10.33 (s, NH), 9.17 (s, NH), 8.25 (d, 1H),7.73 (d, 2H), 7.59 (d, 1H), 7.47 (m, 3H), 7.30 (d, 1H), 7.23 (s, 1H),7.07 (d, 1H), 6.92 (s, 1H), 6.47 (m, 2H), 6.27 (d, 1H), 5.77 (d, 1H),5.00 (m, 1H), 3.62 (m, 1H), 3.44 (m, 3H), 2.51 (m, 2H); MS (ESI⁺): m/z =524.2 [M + H]⁺. 36

¹H-NMR (300 MHz, DMSO-d₆) δ 10.33 (s, NH), 9.13 (s, NH), 8.24 (d, 1H),7.96 (s, 1H), 7.72 (t, 1H), 7.68 (d, 1H), 7.45 (t, 1H), 7.43 (m, 2H),7.29 (d, 1H), 7.22 (s, 1H), 7.05 (dd, 1H), 6.91 (s, 1H), 6.42 (m, 3H),6.26 (dd, 1H), 5.75 (dd, 1H), 4.99 (m, 1H), 3.61 (m, 1H), 3.41 (m, 3H),2.49 (m, 2H); MS (ESI⁺): m/z = 524.2 [M + H]⁺

TABLE 1f Example Structure Analysis data 37

¹H-NMR (300 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.22 (s, 1H), 8.26 (d, 1H),7.70 (s, 1H), 7.64 (m, 1H), 7.47 (d, 1H), 7.41 (m, 2H), 7.31 (d, 1H),7.05 (d, 1H), 6.71 (m, 2H), 6.44 (m, 1H), 6.26 (m, 1H), 5.78 (m, 1H),2.96 (t, 4H), 1.59 (m, 4H), 1.50 (m, 2H); MS (ESI⁺): m/z = 472.10 [M +H]⁺. 38

¹H-NMR (300 MHz, DMSO-d₆) δ 10.37 (s, 1H), 9.27 (s, 1H), 8.29 (d, 1H),7.71 (d, 1H), 7.64 (d, 1H), 7.48 (m, 2H), 7.34 (d, 1H), 7.08 (d, 1H),6.74 (m, 2H), 6.45 (m, 1H), 6.27 (d, 1H), 5.80 (d, 1H), 3.72 (m, 4H),2.98 (m, 4H); MS (ESI⁺): m/z = 515 [M + H]⁺. 39

¹H-NMR (300 MHz, DMSO-d₆) δ 10.39 (s, 1H), 9.25 (s, 1H), 8.29 (d, 1H),7.73 (m, 1H), 7.66 (m, 1H), 7.49 (d, 1H), 7.44 (m, 2H), 7.34 (d, 1H),7.09 (m, 1H), 6.73 (m, 2H), 6.47 (m, 1H), 6.30 (m, 1H), 5.81 (m, 1H),4.67 (d, 1H), 3.59 (m, 1H), 3.40 (m, 2H), 2.71 (m, 2H), 1.82 (m, 2H),1.50 (m, 2H); MS (ESI⁺): m/z = 488.4 [M + H]⁺. 40

¹H-NMR (300 MHz, CD₃OD) δ 8.05 (S, 1H), 7.63 (d, 1H), 7.34 (m, 3H), 6.97(d, 2H), 6.70 (S, 2H), 6.28 (m, 2H), 5.69 (d, 1H), 3.49 (s, 2H), 3.01(m, 4H) 1.58 (m, 1H), 134 (m, 4H); MS (ESI⁺): m/z = 501.1 [M + H]⁺. 41

¹H-NMR (300 MHz, CDCl₃) δ 7.80 (d, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 7.48(s, 1H), 7.44 (t, 1H), 7.40 (d, 2H), 7.25 (m, 1H), 7.05 (m, 1H), 6.82(m, 3H), 6.45 (d, 1H), 6.30 (m, 1H), 5.77 (m, 1H), 3.55 (d, 2H), 2.62(t, 2H), 2.27 (s, 6H), 2.20 (d, 2H), 1.82 (m, 3H), 1.37 (m, 2H); MS(ESI⁺): m/z = 529 [M + H]⁺. 42

¹H-NMR (300 MHz, DMSO-d₆) δ 10.35 (s, 1H), 9.20 (s, 1H), 8.25 (d, 1H),7.68 (m, 1H), 7.61 (m, 1H), 7.44 (t, 1H), 7.37 (m, 2H), 7.30 (d, 1H),7.05 (m, 1H), 6.68 (m, 2H), 6.43 (m, 1H), 6.25 (m, 1H), 5.77 (m, 1H),3.48 (d, 2H), 2.55 (m, 2H), 2.34 (m, 4H), 2.17 (d, 2H), 1.85 (m, 2H),1.57 (m, 5H), 1.42 (m, 4H); MS (ESI⁺): m/z = 569 [M + H]⁺. 43

¹H-NMR (300 MHz, CD₃OD) δ 8.04 (s, 1H), 7.66 (s, 1H), 7.35 (m, 3H), 7.03(d, 2H), 6.81 (d, 2H), 6.38 (m, 2H), 5.78 (d, 1H), 3.50 (t, 2H), 3.01(m, 4H) 1.49 (m, 1H), 1.43 (m, 2H), 1.34 (m, 4H); MS (ESI⁺): m/z = 515.2[M + H]⁺.

TABLE 1g Example Structure Analysis data 44

¹H-NMR (300 MHz, DMSO-d₆) δ 12.17 (brs, 1H), 10.31 (brs, 1H), 9.23 (brs,1H), 8.25 (d, 1H), 7.69 (s, 1H), 7.62 (d, 1H), 7.47-7.38 (m, 3H), 7.30(d, 1H), 7.04 (d, 1H), 6.70 (d, 2H), 6.44-6.38 (m, 1H), 6.25 (dd, 1H),5.78 (d, 1H), 3.42 (d, 2H), 2.48-2.35 (m, 3H), 1.89-1.85 (m, 2H),1.63-1.56 (m, 2H); MS (ESI⁺): m/z = 516.16 [M + H]⁺. 45

¹H-NMR (300 MHz, DMSO) δ 10.35 (s, NH), 9.22 (s, NH), 8.31 (d, 1H), 7.69(s, 1H), 7.48 (d, 2H), 7.39-7.31 (m, 3H), 7.28 (d, 1H), 7.07 (m, 1H),6.73 (d, 2H), 6.48 (m, 1H), 6.29 (m, 1H), 5.79 (m, 1H), 3.55 (d, 2H),3.04 (s, 3H), 2.72 (s, 3H), 2.67-2.57 (m, 3H), 1.67 (m, 4H); MS (ESI⁺):m/z = 543.0 [M + H]⁺. 46

¹H-NMR (300 MHz, CD3OD) δ 8.08 (d, 1H), 7.80 (s, 1H), 7.68 (m, 2H), 7.43(t, 1H), 7.39 (m, 2H), 7.27 (m, 2H), 7.06 (d, 1H), 7.03 (s, 1H), 6.87(d, 2H), 6.44 (m, 2H), 5.81 (m, 1H), 4.23 (m, 1H), 3.68 (d, 2H), 2.84(t, 2H), 2.24 (m, 4H); MS (ESI⁺): m/z = 538.2 [M + H]⁺. 47

¹H-NMR (300 MHz, CDCl3) δ 8.40 (s, NH), 7.77 (d, 1H), 7.68 (s, 1H), 7.63(d, 1H), 7.33 (t, 1H), 7.32 (d, 2H), 7.21 (d, 1H), 7.11 (s, NH), 7.01(d, 1H), 6.98 (d, 2H), 6.43 (m, 2H), 5.68 (m, 1H), 3.49 (m, 2H), 2.73(m, 4H), 2.56 (t, 2H), 2.27 (m, 1H), 2.04 (m, 2H), 1.92 (m, 4H), 1.74(m, 2H); MS (ESI⁺): m/z = 541.0 [M + H]⁺. 48

¹H-NMR (300 MHz, CD₃OD) δ 8.05 (d, 1H), 7.64 (d, 2H), 7.47 (t, 1H), 7.35(d, 2H), 7.23 (d, 1H), 7.04 (d, 1H), 6.81 (d, 2H), 6.40 (m, 2H), 5.77(dd, 1H), 4.78 (m, 2H), 3.61 (m, 2H), 3.25 (m, 2H), 2.67 (m, 2H), 2.56(m, 2H), 2.46 (m, 1H), 2.01 (m, 2H), 1.71 (m, 2H), 1.51 (m, 2H); MS(ESI⁺): m/z = 555.0 [M + H]⁺. 49

¹H-NMR (300 MHz, DMSO-d₆) δ 10.3 (s, 1H), 9.13 (s, 1H), 8.17 (d, 1H),7.65 (s, 1H), 7.53 (d, 1H), 7.34 (d, 1H), 7.32 (m, 2H), 7.29 (d, 1H),6.98 (d, 1H), 6.63 (d, 2H), 6.34 (dd, 1H), 6.21 (d, 1H), 3.50 (m, 4H),3.43 (m, 1H), 3.20 (brs, 1H); MS (ESI⁺): m/z = 556.68 [M + H]⁺. 50

¹H-NMR (300 MHz, DMSO-d₆) δ 10.34 (s, 1H), 9.23 (s, 1H), 8.25 (d, 1H),7.68 (s, 1H), 7.62 (d, 1H), 7.45 (d, 1H), 7.40 (m, 2H), 7.30 (d, 1H),7.04 (m, 1H), 6.70 (m, 2H), 6.43 (m, 1H), 6.26 (m, 1H), 5.77 (m, 1H),3.46 (m, 2H), 2.56 (m, 1H), 2.50 (m, 6H), 2.33 (m, 4H), 2.29 (m, 2H),1.80 (m, 2H), 1.48 (m, 2H), 0.97 (t, 3H); MS (ESI⁺): m/z = 584.3 [M +H]⁺.

TABLE 1h Example Structure Analysis data 51

¹H-NMR (300 MHz, CDCl₃) δ 7.85 (d, 1H), 7.67 (s, 1H), 7.56 (m, 1H), 7.43(m, 3H), 7.31 (s, 1H), 7.21 (m, 2H), 7.06 (d, 1H), 6.46 (m, 1H), 6.27(m, 1H), 5.98 (m, 1H), 5.78 (d, 1H), 3.12 (m, 2H), 2.69 (t, 2H), 2.57(m, 2H), 2.42 (s, 3H); MS (ESI⁺): m/z = 484.1 [M + H]⁺. 52

¹H-NMR (300 MHz, CDCl₃) δ 8.13 (s, 1H), 7.83 (d, 1H), 7.76 (s, 1H), 7.52(m, 1H), 7.39 (t, 1H), 7.34 (d, 2H), 7.25 (d, 1H), 7.11 (s, 1H), 7.02(d, 3H), 6.36 (m, 2H), 5.74 (d, 1H), 3.01 (m, 2H), 2.41 (m, 1H), 2.37(s, 3H), 2.31 (m, 2H), 2.09 (m, 2H), 1.85 (m, 2H); MS (ESI⁺): m/z =486.2 [M + H]⁺. 53

¹H-NMR (3(00 MHz, CDCl₃) δ 8.27 (s, 1H), 7.81 (d, 1H), 7.75 (s, 1H),7.51 (d, 1H), 7.33 (m, 3H), 7.25 (d, 1H), 7.14 (s, 1H), 7.02 (s, 2H),6.99 (s, 1H), 6.38 (m, 2H). 5.71 (m, 1H), 3.11 (m. 2H), 2.51 (q, 2H),2.44 (m, 1H), 2.07 On. 2H), 1.80 (m, 4H), 1.16 (t, 3H); MS (ESI⁺): m/z =500.2 [M + H]⁺. 54

¹H-NMR (300 MHz, CDCl₃) δ 9.63 (s, 1H), 8.21 (s, 1H), 7.84 (d, 1H), 7.48(d, 1H), 7.35 (t, 1H), 7.20 (m, 4H), 6.94 (m, 3H), 6.67 (m, 1H), 6.39(m, 1H), 5.65 (m, 1H), 3.35 (m, 2H), 3.28 (m, 1H), 2.67 (m, 2H), 2.50(m, 1H), 2.40 (m, 2H), 1.84 (m, 2H), 1.35 (d, 6H); MS (ESI⁺): m/z =514.2 [M + H]⁺. 55

¹H-NMR (300MHz, CDCl₃) δ 7.83 (d, 1H), 7.78 (s, 1H), 7.65 (s, 1H), 7.56(d, 1H), 7.43 (m, 3H), 7.27 (d, 1H), 7.11 (s, 1H), 7.04 (m, 3H), 6.45(m, 1H), 6.27 (m, 1H), 5.76 (m, 1H), 2.94 (m, 2H), 2.79 (m, 1H), 2.32(s, 3H), 2.02 (m, 3H), 1.85 (m, 2H), 1.36 (m, 1H); MS (ESI⁺): m/z =486.2 [M + H]⁺. 56

¹H-NMR (300 MHz, DMSO-d₆) δ 10.39 (s, NH), 9.67 (s, NH), 8.33 (d, 1H),8.08 (s, 1H), 7.73 (m, 3H), 7.58 (m, 2H), 7.47 (t, 1H), 7.34 (m, 3H),7.08 (m, 2H), 6.43 (m, 1H), 6.27 (m, 1H), 5.74 (m, 1H); MS (ESI⁺): m/z =455.0 [M + H]⁺. 57

¹H-NMR (300 MHz, DMSO-d₆) δ 10.34 (s, 1H), 9.08 (s, 1H), 8.35 (d, 1H),8.23 (m, 1H), 7.65 (d, 1H), 7.57 (m, 1H), 7.42 (m, 2H), 7.28 (d, 1H),7.04 (m, 1H), 6.42 (m, 2H), 6.28 (m, 2H), 6.02 (d, 1H), 5.74 (dd, 1H),2.67 (m, 4H), 2.16 (m, 2H), 1.84 (m, 2H), 1.33 (m, 2H), 0.97 (m, 6H) MS(ESI⁺): m/z = 475.2 [M + H]⁺.

TABLE 1i Example Structure Analysis data 58

¹H-NMR (300 MHz, DMSO-d₆) δ 10.34 (s, 1H), 9.02 (s, 1H), 8.22 (d, 1H),7.68 (d, 1H), 7.62 (m, 1H), 7.44 (m, 1H), 7.27 (m, 2H), 7.04 (m, H),6.42 (m, 3H), 6.24 (dd, 1H), 5.76 (dd, 1H), 3.03 (m, 2H), 2.49~2.32 (m,10H), 2.15 (s, 3H); MS (ESI⁺): m/z = 530.2 [M + H]⁺. 59

¹H-NMR (300 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.00 (s, 1H), 8.23 (d, 1H),7.63 (m, 2H), 7.40 (m, 2H), 7.27 (m, 2H), 7.08 (m, 1H), 6.87 (m, 1H),6.44 (m, 2H), 6.29 (d, 1H), 5.77 (d, 1H), 5.00 (d, 1H), 3.05 (m, 1H),2.70 (m, 2H), 2.16 (s, 3H), 1.95 (m, 2H), 1.82 (m, 2H), 1.31 (m, 2H); MS(ESI⁺): m/z = 501.2 [M + H]⁺. 60

¹H-NMR (300 MHz, DMSO-d₆) δ 10.39 (brs, 1H), 9.12 (brs, 1H), 8.97 (brs,1H), 8.26 (d, 1H), 7.73 (s, 1H), 7.61 (d, 1H), 7.49-7.31 (m, 4H),7.10-7.06 (m, 1H). 6.57-6.41 (m, 3H), 6.30- 6.25 (m, 1H), 5.81-5.77 (m,1H); MS (ESI⁺): m/z = 405.09 [M + H]⁺. 61

¹H-NMR (300 MHz, DMSO-d₆) δ 10.34 (s, NH), 9.30 (s, NH), 8.28 (d, 1H),7.72 (s, 1H), 7.60 (dd, 1H), 7.48-7.43 (m, 3H), 7.32 (d, 1H), 7.08 (dd,1H), 6.72 (d, 2H), 6.44 (m, 1H), 6.29 (m, 1H), 5.79 (m, 1H), 4.00 (m,2H), 3.63 (m, 2H), 3.27 (s, 3H); MS (ESI⁺): m/z = 463.2 [M + H]⁺. 62

¹H-NMR (300 MHz, DMSO-d₆) δ 10.37 (s, 1H), 9.31 (s, 1H), 8.28 (d, 1H),7.72 (s, 1H), 7.59 (d, 1H), 7.44 (m, 3H), 7.33 (d, 1H), 7.07 (d, 1H),6.69 (d, 2H), 6.39 (dd, 1H), 6.29 (d, 1H), 5.79 (d, 1H), 3.95 (t, 2H),2.60 (t, 2H), 2.22 (s, 6H); MS (ESI⁺): m/z = 476.2 [M + H]⁺. 63

¹H-NMR (300 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.30 (s, 1H), 8.27 (d, 1H),7.72 (s, 1H), 7.60 (d, 1H), 7.45 (m, 3H), 7.32 (d, 1H), 7.07 (d, 1H),6.69 (d, 2H), 6.41 (dd, 1H), 6.25 (d, 1H), 5.76 (d, 1H), 3.90 (t, 2H),3.34 (m, 4H), 2.70 (t, 2H), 2.50 (m, 4H), 1.03 (s, 6H); MS (ESI⁺): m/z =504.2 [M + H]⁺. 64

¹H-NMR (300 MHz, DMSO-d₆) δ 10.38 (s, 1H), 9.33 (s, 1H), 8.27 (d, 1H),7.72 (s, 1H), 7.60 (d, 1H), 7.47 (m, 3H), 7.33 (d, 1H), 7.05 (d, 1H),6.70 (m, 2H), 6.44 (dd, 1H), 6.25 (d, 1H), 5.77 (d, 1H), 3.95 (t, 2H),2.72 (t, 2H), 2.50 (m, 4H), 1.67 (m, 4H); MS (ESI⁺): m/z = 502.2 [M +H]⁺.

TABLE 1j Example Structure Analysis data 65

¹H-NMR (300 MHz, CDCl₃) δ 8.14 (s, 1H), 7.80 (d, 1H), 7.61 (s, 1H), 7.48(d, 1H), 7.34 (m, 3H), 7.24 (m, 2H), 6.99 (d, 1H), 6.72 (d, 2H), 6.39(d, 1H), 6.25 (dd, 2H), 5.72 (d, 1H), 4.03 (t, 2H), 3.71 (m, 4H), 2.75(t, 2H), 2.56 (m, 4H); MS (ESI⁺): m/z = 518.4 [M + H]⁺. 66

¹H-NMR (300 MHz, CDCl₃) δ 7.82 (d, 1H), 7.63 (s, 1H), 7.43 (m, 6H), 7.04(d, 1H), 6.89 (s, 1H), 6.76 (m, 2H), 6.45 (d, 1H), 6.26 (m, 1H), 5.74(d, 1H), 4.23 (m, 2H), 2.77 (m, 2H), 2.47 (q, 2H), 2.33 (m, 2H), 2.04(m, 2H), 1.80 (m, 2H), 1.12 (t, 3H); MS (ESI⁺): m/z = 516.3 [M + H]⁺. 67

¹H-NMR (300 MHz, DMSO-d₆) δ 10.38 (brs, 1H), 9.92 (brs, 1H), 8.34 (d,1H), 7.87-7.31 (m, 8H), 7.09 (d, 1H), 6.46-6.37 (m, 1H), 6.23 (d, 1H),5.75 (d, 1H), 3.91 (t, 4H), 1.20-1.12 (m, 6H); MS (ESI⁺): m/z = 525.13[M + H]⁺. 68

¹H-NMR (300 MHz, DMSO-D₆) δ 10.39 (s, 1H), 9.86 (s, 1H), 8.35 (d, 1H),7.77 (m, 2H), 7.58 (m, 1H), 7.40 (m, 4H), 7.11 (d, 1H), 6.43 (dd, 1H),6.25 (d, 1H), 5.77 (d, 1H), 2.65 (s, 3H); MS (ESI⁺): m/z = 451.1 [M +H]⁺. 69

¹H-NMR (300 MHz, DMSO-D₆) δ 10.40 (s, 1H), 10.09 (s, 1H), 8.55 (m, 1H),7.80 (m, 3H), 7.62 (m, 3H), 7.50 (m, 2H), 7.10 (m, 1H), 6.54 (dd, 1H),6.28 (d, 1H), 5.79 (d, 1H), 3.10 (s, 3H); MS (ESI⁺): m/z = 467.5 [M +H]⁺. 70

¹H-NMR (300 MHz, DMSO-d₆) δ 10.32 (s, 1H), 9.86 (s, 1H), 8.35 (d, 1H),7.70 (m, 3H), 7.54 (m, 3H), 7.45 (m, 2H), 7.12 (s, 2H), 6.42 (m, 1H),6.23 (dd, 1H), 5.75 (dd, 1H); MS (ESI⁺): m/z = 468.1 [M + H]⁺. 71

¹H-NMR (300MHz, DMSO-d₆) δ 10.38 (s, 1H), 10.02 (s, 1H), 8.36 (d, 1H),7.78 (m, 3H), 7.68 (m, 2H), 7.57 (m, 2H), 7.36 (m, 1H), 7.10 (m, 1H),6.48 (m, 1H), 6.21 (dd, 1H), 5.75 (dd, 1H), 1.99 (m, 1H), 0.41 (m, 2H),0.34 (m, 2H); MS (ESI⁺): m/z = 508.1 [M+H]⁺.

TABLE 1k Example Structure Analysis data 72

¹H-NMR (300 MHz, DMSO-d₆) δ 10.37 (s, 1H), 9.97 (s, 1H), 8.30 (d, 1H),7.76 (m, 2H), 7.73-7.21 (m, 6H), 7.09 (m, 1H), 6.40 (m, 1H), 6.21 (dd,1H), 5.74 (dd, 1H), 2.75 (m, 2H), 2.22 (m, 2H), 2.04 (s, 6H); MS (ESI⁺):m/z = 539.2 [M + H]⁺. 73

¹H-NMR (300 MHz, DMSO-d₆) δ 10.40 (s, 1H), 10.00 (s, 1H), 8.37 (d, 1H),7.74 (m, 3H), 7.46 (m, 6H), 7.12 (d, 1H), 6.44 (dd, 1H), 6.25 (d, 1H),5.77 (d, 1H), 2.78 (m, 1H), 2.50 (m, 2H), 1.63 (m, 2H), 1.46 (m, 2H),1.33 (m, 2H); MS (ESI⁺): m/z = 565.2 [M + H]⁺. 74

¹H-NMR (300 MHz, DMSO-d₆) δ 10.39 (s, 1H), 10.01 (s, 1H), 8.37 (d, 1H),7.75 (m, 2H), 7.61-7.43 (m, 6H), 7.12 (m, 1H), 6.40 (m, 1H), 6.24 (dd,1H), 5.76 (dd, 1H), 2.77 (m, 2H), 2.60 (m, 2H), 1.49 (m, 2H), 1.25 (m,2H), 1.18 (m, 2H), 0.87 (m, 6H); MS (ESI⁺): m/z = 593.2 [M + H]⁺. 75

¹H-NMR (300 MHz, DMSO-d₆) δ 10.40 (s, 1H), 10.14 (s, 1H), 8.38 (d, 1H),7.78 (m, 3H), 7.59 (m, 1H), 7.50 (m, 1H), 7.44 (m, 4H), 7.10 (m, 1H),6.38 (m, 1H), 6.22 (dd, 1H), 5.76 (dd, 1H), 3.59 (s, 4H), 2.92 (s, 4H);MS (ESI⁺): m/z = 538.1 [M + H]⁺. 76

¹H-NMR (300 MHz, DMSO-d₆) δ 10.41 (s, 1H), 10.13 (s, 1H), 8.39 (d, 1H),7.60 (m, 8H), 7.10 (m, 1H), 6.41 (m, 1H), 6.25 (m, 1H), 5.75 (m, 1H),2.76 (m, 4H), 2.38 (m, 4H), 2.29 (q, 2H), 0.91 (t, 3H). MS (ESI⁺): m/z =565.4 [M + H]⁺. 77

¹H-NMR (300 MHz, DMSO-d₆) δ 10.39 (brs, 1H), 9.81 (brs, 1H), 8.37 (d,1H), 7.78-7.71 (m, 4H), 7.62-7.58 (m, 1H), 7.52- 7.49 (m, 2H), 7.17-7.09(m, 1H), 6.48-6.39 (m, 1H), 6.25 (d, 1H), 5.77 (d, 1H), 2.46 (s, 3H); MS(ESI⁺): m/z = 431.11 [M + H]⁺. 78

¹H-NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.79 (s, 1H), 8.34 (d, 1H),8.16(d, 1H), 7.67(s, 1H), 7.57(m, 4H), 7.46 (m, 1H), 7.42 (m, 1H), 7.11(m, 1H), 6.48 (m, 1H), 6.28 (dd, 1H), 5.75 (dd, 1H), 2.74 (s, 3H); MS(ESI⁺): m/z = 446.1 [M + H]⁺.

TABLE 1l Example Structure Analysis data 79

H-NMR (300 MHz, DMSO-d6) δ 10.4 (brs, 1H), 9.80 (brs, 1H), 8.36-8.34 (m,1H), 7.87 (s, 1H), 7.64-7.43 (m, 5H), 7.41 (d, 2H), 7.13-7.10 (m, 1H),6.46-6.41 (m, 1H), 6.28-6.23 (m, 1H), 5.79- 5.75 (m, 1H), 3.31-3.17 (m,2H), 2.63-2.50 (m, 2H), 2.31 (s, 6H); MS (ESI⁺): m/z = 503.1 [M + H]⁺.80

¹H-NMR (300 MHz, CDCl₃) δ 9.02 (s, 1H), 7.85 (d, 2H), 7.83 (d, 3H), 7.46(d, 1H), 7.26 (t, 2H), 6.96 (d, 1H), 6.39 (d, 1H), 5.68 (dd, 1H), 3.70(bs, 1H), 3.61 (d, 1H), 2.87 (s, 2H), 2.79 (bs, 4H), 1.89 (bs, 4H); MS(ESI⁺): m/z = 529.4 [M + H]⁺. 81

¹H-NMR (300 MHz, DMSO-d₆) δ 10.38 (s, 1H), 9.79 (s, 1H), 8.35 (d, 1H),8.02 (d, 2H), 7.77 (s, 1H), 7.51 (m, 4H), 7.45 (m, 1H), 7.42 (m, 1H),6.43 (dd, 1H), 6.28 (d, 1H), 5.78 (d, 1H), 3.96 (m, 1H), 3.86 (m, 2H),3.38 (m, 2H), 1.74 (m, 2H), 1.58 (m, 2H); MS (ESI⁺): m/z = 516.2 [M +H]⁺. 82

¹H-NMR (300 MHz, DMSO-d₆) δ 10.40 (s, 1H), 9.79 (s, 1H), 8.34 (d, 1H),8.96 (d, 1H), 7.78 (s, 1H), 7.64 (m, 4H), 7.47 (m, 2H), 7.12 (d, 1H),6.42 (dd, 1H), 6.28 (d, 1H), 5.77 (d, 1H), 3.69 (m, 1H), 2.75 (m, 2H),2.16 (s, 3H), 1.92 (m, 2H), 1.73 (m, 2H), 1.55 (m, 2H); MS (ESI⁺): m/z =529.2 [M + H]⁺. 83

¹H-NMR (300 MHz, DMSO-d₆) δ 10.38 (s, 1H), 9.76 (s, 1H), 8.34 (d, 1H),7.92 (d, 1H), 7.77 (s, 1H), 7.60 (m, 5H), 7.41 (m, 2H), 6.41 (dd, 1H),6.25 (d, 1H), 5.76 (d, 1H), 3.68 (m, 1H), 2.77 (m, 2H), 2.64 (m, 1H),2.14 (m, 2H), 1.75 (m, 2H), 1.48 (m, 2H), 0.94 (d, 6H); MS (ESI⁺): m/z =557.2 [M + H]⁺. 84

¹H-NMR (300 MHz, DMSO-d₆) δ 10.34 (s, 1H), 9.74 (s, 1H), 8.3l (d, 1H),7.60 (s, 1H), 7.58 (m, 3H), 7.48 (m, 1H), 7.41 (m, 1H), 7.18 (m, 2H),7.08 (m, 1H), 6.47 (m, 1H), 6.27 (dd, 1H), 5.75(dd, 1H), 2.92 (s, 6H);MS (ESI⁺): m/z = 460.1 [M + H]⁺. 85

¹H-NMR (300 MHz, DMSO-d₆) δ 10.42 (brs, 1H), 9.78 (brs, 1H), 8.36-8.34(m, 1H), 7.78 (s, 1H), 7.62-7.40 (m, 5H), 7.26 (d, 211), 7.12-7.09 (m,1H), 6.48-6.43 (m, 1H), 6.28-6.22 (m, 1H), 5.79-5.75 (m, 1H), 3.52-3.48(m, 2H), 3.17-2.90 (m, 3H), 2.30- 2.17 (m, 3H), 1.93-1.73 (m, 2H); MS(ESI⁺): m/z = 515.2 [M + H]⁺.

TABLE 1m Example Structure Analysis data 86

¹H-NMR (300 MHz, DMSO-d₆) δ 10.5 (brs, 1H), 9.80 (brs, 1H), 8.30-8.20(m, 1H), 7.78 (s, 1H), 7.60-7.40 (m, 5H), 7.35(d, 2H), 7.20 (m, 1H),6.50-6.40 (m, 1H), 6.30-6.20 (m, 1H), 5.80-5.70 (m, 1H), 3.60-3.50 (m,4H), 2.80-2.60 (m, 1H), 2.30-2.00 (m, 7H), 1.80-1.60 (m, 1H); MS (ESI⁺):m/z = 529.1 [M + H]⁺. 87

¹H-NMR (300 MHz, DMSO-d₆) δ 10.50 (brs, 1H), 9.80 (brs, 1H), 8.40-8.35(m, 1H), 7.80 (s, 1H), 7.60-7.30 (m, 4H), 7.25 (d, 1H), 7.10-7.00 (m,3H), 6.40-6.35 (m, 1H), 6.20-6.15 (m, 1H), 5.75-5.80 (m, 1H), 4.70 (s,1H), 4.10-4.05 (m, 1H), 3.90-3.70 (m, 2H), 3.30 (s, 1H), 3.20-3.10 (m,4H); MS (ESI⁺): m/z = 516.2 [M + H]⁺. 88

¹H-NMR (300 MHz, DMSO-d₆) δ 10.36-(s, 1H), 9.76 (s, 1H), 8.35 (d, 1H),7.76 (d, 1H), 7.58 (m, 3H), 7.45 (m, 1H), 7.39 (m, 1H), 7.15 (m, 2H),7.08 (m, 1H), 6.47 (m, 1H), 6.22 (dd, 1H), 5.75 (dd, 1H), 3.58 (m, 4H),3.46 (m, 4H); MS (ESI⁺): m/z = 502.2 [M + H]⁺. 89

¹H-NMR (300 MHz, DMSO-d₆) δ 10.34 (s, 1H), 9.75 (s, 1H), 8.35 (d, 1H),7.88 (d, 1H). 7.76 (d, 1H), 7.57 (m, 4H), 7.46 (m, 1H), 7.42 (m, 1H),7.10 (m, 1H), 6.48 (m, 1H), 6.28 (dd, 1H), 5.78 (dd, 1H), 3.45 (m, 4H),2.28 (m, 4H), 2.10 (s, 3H); MS (ESI⁺): m/z = 515.2 [M + H]⁺. 90

¹H-NMR (300 MHz, CDCl₃) δ 8.90 (s, 1H), 7.76 (d, 1H), 7.74 (s, 1H), 7.51(s, 1H), 7.40 (s, 1H), 7.29-7.22 (m, 2H), 7.14 (d, 2H), 6.85 (d, 1H),6.29 (d, 1H), 6.24 (s, 1H), 5.60 (d, 1H), 3.66-2.31 (m, 4H), 2.35 (t,2H), 2.33-2.31 (m, 4H), 1.00 (t, 3H); MS (ESI⁺): m/z = 528.63 [M + H]⁺.91

¹H-NMR (300 MHz, CDCl₃) δ 8.27 (d, 1H), 7.79-7.77 (d, 1H), 7.57 (m, 1H),7.34-7.09 (m, 5H), 6.99 (m, 1H), 6.37.-6.31 (m, 1H), 6.20- 6.15 (m, 1H),5.68-5.67 (m, 1H), 5.77-5.74 (m, 1H), 4.16-4.07 (m, 4H) 2.86-2.82 (m,2H), 2.47 (m, 4H), 2.19 (m, 3H), 1.95 (m, 4H), 1.88-1.39 (m, 5H); MS(ESI⁺): m/z = 598.2 [M + H]⁺. 92

¹H-NMR (300 MHz, CDCl₃) δ 9.02 (s, 1H), 7.85 (d, 2H), 7.83 (d, 3H), 7.46(d, 1H), 7.26 (t, 2H), 6.96 (d, 1H), 6.39 (d, 1H), 5.68 (dd, 1H), 3.70(bs, 1H), 3.61 (d, 1H), 2.87 (s, 2H), 2.79 (bs, 4H), 1.89 (bs, 4H); MS(ESI⁺): m/z = 529.4 [M + H]⁺.

TABLE 1n Example Structure Analysis data 93

¹H-NMR (300 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.96 (s, 1H), 8.33 (d, 1H),7.76 (m, 2H), 7.68 (m, 3H), 7.49 (m, 1H), 7.42 (m, 1H), 7.40 (m, 1H),7.08 (m, 1H), 6.40 (m, 1H), 6.20 (dd, 1H), 5.73 (dd, 1H), 4.20 (t, 2H),2.30 (t, 2H), 2,12 (s, 6H), 1.76 (m, 2H); MS (ESI⁺): m/z = 518.2 [M +H]⁺. 94

¹H-NMR (300 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.58 (s, 1H), 8.32 (d, 1H),7.73 (s, 1H), 7.60 (m, 3H), 7.45 (t, 1H), 7.40 (d, 1H), 6.43 (dd, 1H),6.22 (d, 1H), 5.78 (d, 1H), 3.85 (dd, 2H), 2.27 (s, 3H); MS (ESI⁺): m/z= 465.1 [M + H]⁺. 95

¹H-NMR (300 MHz, DMSO-d₆) δ 10.38 (s, 1H), 9.62 (s, 1H), 8.32 (d, 1H),7.73 (t, 1H), 7.62 (m, 3H), 7.47 (t, 1H), 7.40 (d, 1H), 7.16 (d, 2H),7.10 (m, 1H), 6.40 (m, 1H), 6.25 (m, 1H), 5.77 (m, 1H), 4.33 (s, 2H),2.84 (s, 3H); MS (ESI⁺): m/z = 481.1 [M + H]⁺. 96

¹H-NMR (300 MHz, CDCl₃) δ 10.36 (s, 1H), 9.45 (s, 1H), 8.30 (d, 1H),7.74 (s, 1H), 7.48 (m, 4H), 7.36 (d, 1H), 7.07 (m, 3H), 6.40 (dd, 1H),6.25 (d, 1H), 5.77 (d, 1H), 3.30 (m, 2H), 2.95 (m, 2H), 2.54 (s, 3H); MS(ESI⁺): m/z = 479.1 [M + H]⁺. 97

¹H-NMR (300 MHz, DMSO-d₆) δ 10.39 (s, 1H), 9.48 (s, 1H), 8.29 (d, 1H),7.73 (s, 1H), 7.48 (m, 4H), 7.35 (d, 1H), 7.05 (m, 3H), 6.42 (m, 1H),6.25 (m, 1H), 5.76 (m, 1H), 3.31 (m, 2H), 2.94 (s, 3H), 2.87 (m, 2H); MS(ESI⁺): m/z = 495.1 [M + H]⁺. 98

¹H-NMR (300 MHz, DMSO-d₆): δ 10.36 (brs, 1H), 9.40 (brs, 1H), 8.31-8.30(d, 1H), 7.72-7.71 (m, 1H), 7.64-7.61 (m, 1H), 7.48-7.43 (m, 3H),7.36-7.34 (d, 1H), 7.09-7.06 (m, 1H), 6.96- 6.93 (m, 2H), 6.43-6.39 (m,1H), 6.29-6.21 (m, 1H), 5.79-5.75 (m, 1H), 2.61 (m, 2H), 2.41 (m, 6H),1.51 (m, 4H), 1.40 (m, 2H); MS (ESI⁺): m/z = 500.2 [M + H]⁺. 99

¹H-NMR (300 MHz, CDCl₃) δ; 7.84 (m, 1H), 7.69 (m, 1H), 7.52 (m, 1H),7.42-7.33 (m, 3H), 7.06-7.00 (m, 4H), 6.47 (dd, 1H), 6.33 (dd, 1H), 5.75(dd, 1H), 2.79-2.45 (m, 14H), 1.12 (t, 3H); MS (ESI⁺): m/z = 529.4 [M +H]⁺.

TABLE 1o Example Structure Analysis data 100

¹H-NMR (300 MHz, CDCl₃) δ 7.82 (t, 1H), 7.65 (s, 1H), 7.57 (m, 1H), 7.39(m, 3H), 7.28 (m, 2H), 7.03 (m, 4H), 6.67 (m, 1H), 6.41 (m, 1H), 5.75(m, 1H), 3.33 (s, 4H), 2.97 (m, 2H), 2.71 (m, 2H), 2.59 (brs, 6H), 1.38(t, 3H); 101

¹H-NMR (300 MHz, DMSO-d₆) δ 10.39 (s, 1H), 9.58 (s, 1H), 8.31 (d, 1H),7.75 (s, 1H), 7.52 (m, 4H), 7.38 (d, 1H), 7.12 (m, 3H), 6.37 (m, 3H),6.11 (m, 1H), 5.75 (d, 1H), 2.98 (d, 2H), 2.15 (s, 6H); MS (ESI⁺): m/z =472.2 [M + H]⁺. 102

¹H-NMR (300 MHz, CDCl₃) δ 8.40 (m, 1H), 7.94 (s, 1H), 7.86 (m, 1H), 7.44(m, 2H), 7.33 (m, 3H), 7.17 (m, 2H), 7.04 (m, 2H), 6.42 (m, 3H), 6.34(m, 1H), 5.71 (m, 1H), 3.24 (d, 2H), 2.47 (m, 4H), 1.75 (m, 4H), 1.54(m, 2H); MS (ESI⁺): m/z = 512.2 [M + H]⁺. 103

¹H-NMR (300 MHz, DMSO-d₆) δ 10.35 (s, 1H), 9.43 (s, 1H), 8.30 (d, 1H),7.89 (d, 1H), 7.71 (s, 1H), 7.45 (m, 3H), 7.36 (d, 1H), 7.05 (m, 3H),6.44 (dd, 1H), 6.25 (d, 1H), 5.76 (d, 1H), 3.43 (m, 1H), 2.70 (m, 2H),2.14 (s, 3H), 1.94 (m, 2H), 1.66 (m, 2H), 1.40 (m, 2H); MS (ESI⁺): m/z =543.3 [M + H]⁺. 104

¹H-NMR (300 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.22 (s, 1H), 8.26 (d, 2H),7.70 (s, 1H), 7.64 (m, 1H), 7.47 (d, 1H), 7.41 (m, 1H), 7.31 (d, 1H),7.05 (d, 2H), 6.71 (m, 1H), 6.44 (m, 1H), 6.26 (m, 2H), 5.78 (m, 1H),2.96 (m, 2H), 1.59 (m, 2H), 1.50 (m, 1H); MS (ESI⁺): m/z = 471.2 [M +H]⁺. 105

¹H-NMR (300 MHz, DMSO-d₆) δ 10.27 (brs, 1H), 9.35 (brs, 1H), 8.18 d,1H), 7.61. (s, 1H), 7.55 (d, 1H), 7.42-7.38 (m, 3H), 7.26-7.24 (d, 1H),6.99 (d, 1H), 6.96-6.92 (m, 2H), 6.34-6.29 (m, 1H), 6.18-6.13 (m, 1H),5.68-5.67 (m, 1H), 3.45-3.44 (m, 2H), 3.13-3.09 (m, 1H), 2.84-2.80 (m,1H), 2.72 (s, 3H), 1.90 (s, 3H); MS (ESI⁺): m/z = 515.2 [M + H]⁺. 106

¹H-NMR (300 MHz, DMSO-d₆) δ 9.47 (s, NH), 8.35 (m, 2H), 8.23 (dd, 1H),7.82-7.75 (m, 2H), 7.38 (d, 1H), 7.09 (m, 1H), 6.92 (m, 1H), 6.58 (m,1H), 4.12 (s, 4H); MS (ESI⁺): m/z = 447.4 [M + H]⁺.

TABLE 1p Example Structure Analysis data 107

¹H-NMR (300 MHz, DMSO-d₆) δ 10.37 (s, 1H), 9.24 (s, 1H), 8.28 (d, 1H),7.73 (m, 1H), 7.60 (m, 1H), 7.47 (dd, 1H), 7.32 (d, 1H), 7.08 (m, 2H),6.82 (m, 1H), 6.57 (m, 1H), 6.42 (dd, 1H), 5.77 (dd, 1H), 4.77 (s, 1H),3.85 (m, 2H), 3.02 (m, 2H), 1.81 (m, 2H); MS (ESI⁺): m/z = 460.1 [M +H]⁺. 108

¹H-NMR (300 MHz, DMSO-d₆) δ 10.50 (brs, 1H), 9.60 (brs, 1H), 8.32-8.30(m, 1H), 7.78-7.77 (m, 1H), 7.62-7.59 (m, 1H), 7.48-7.39 (m, 3H),7.36-7.34 (m, 1H), 7.07-7.01 (m, 2H), 6.46- 6.41 (m, 1H), 6.25-6.20 (m,1H), 5.76-5.72 (m, 1H), 3.12 (s, 3H), 2.36 (m, 2H), 2.04-2.02 (m, 2H),1.93-1.89 (m, 2H); MS (ESI⁺): m/z = 486.1 [M + H]⁺. 109

¹H-NMR (300 MHz, DMSO-d₆) δ 9.47 (s, 1H), 8.28 (d, 1H), 7.80 (d, 1H),7.73 (s, 1H), 7.57 (d, 1H), 7.45 (m, 2H), 7.33 (d, 1H), 7.20 (m, 1H),7.07 (m, 1H), 6.41 (m, 1H), 6.23 (m, 1H), 5.75 (m, 1H), 4.07 (t, 2H),3.12 (s, 2H), 2.91 (m, 2H), 2.23 (s, 6H); MS (ESI⁺): m/z = 515.1 [M +H]⁺. 110

¹H-NMR (300 MHz, DMSO-d₆) δ 10.35 (s, 1H), 9.68 (s, 1H), 8.76 (s, 1H),8.50 (d, 1H), 8.06 (d, 2H), 7.75 (s, 1H), 7.56 (m, 1H), 7.38 (m, 2H),7.05 (m, 2H), 6.42 (m, 1H), 6.23 (dd, 1H), 5.70 (dd, 1H); MS (ESI⁺): m/z= 390.10 [M + H]⁺. 111

¹H-NMR (300 MHz, DMSO-d₆) δ 10.40 (s, 1H), 9.43 (bm, 1H), 8.29 (d, 1H),7.78 (m, 2H), 7.64 (d, 1H), 7.48 (t, 1H), 7.33 (d, 1H), 7.21 (m, 3H),7.10 (m, 1H), 6.42 (m, 1H), 6.28 (d, 1H), 6.20 (m, 1H), 5.76 (m, 1H); MS(ESI⁺): m/z = 441.7 [M + H]⁺. 112

¹H-NMR (300 MHz, CDCl₃) δ 8.44 (bs, 1H), 7.96 (d, 1H), 7.94 (d, 1H),7.66 (s, 1H), 7.45 (d, 2H), 7.31 (m, 1H), 7.20 (d, 1H), 6.98 (d, 1H),6.43 (s, 1H), 6.35 (s, 1H), 6.27-6.24 (m, 2H), 5.65 (d, 1H), 3.72 (s,3H), 3.10 (bs, 4H), 2.47 (bs, 4H), 2.45 (dd, 2H), 1.12 (t, 3H); MS(ESI⁺): m/z = 531.2 [M + H]⁺. 113

¹H-NMR (300 MHz, DMSO-d₆) δ 10.35 (s, 1H), 8.26 (d, 1H), 7.71 (m, 2H),7.64 (m, 2H), 7.44 (dd, 1H), 7.31 (d, 1H), 7.07 (m, 1H), 6.59 (m, 1H),6.40 (dd, 1H), 6.29 (m, 2H), 5.77 (dd, 1H), 3.77 (s, 3H), 3.73 (m, 4H),3.03 (m, 4H) MS (ESI⁺): m/z = 504.08 [M + H]⁺.

TABLE 1q Example Structure Analysis data 114

¹H-NMR (300 MHz, DMSO-d₆) δ 10.38 (brs, 1H), 8.31-8.30 (d, 1H),7.84-7.72 (m, 3H), 7.63-7.60 (m, 1H), 7.48-7.43 (t, 1H), 7.36-7.34 (m,1H), 7.09-7.06 (m, 1H), 6.84 (s, 1H), 6.61-6.58 (m, 1H), 6.49-6.40 (m,1H), 6.29-6.24 (m, 1H), 5.80-5.76 (m, 1H), 3.81 (s, 3H), 3.18 (m, 2H),2.54 (s, 3H), 1.91-1.71 (m, 6H); MS (ESI⁺): m/z = 516.2 [M + H]⁺. 115

¹H-NMR (300 MHz, DMSO-d₆) δ 10.64 (brs, 1H), 8.31-8.29 (m, 1H),7.82-7.76 (m, 3H0, 7.70 (m, 1H), 7.44 (m, 1H), 7.35- 7.33 (m, 1H), 7.05(m, 1H), 6.85 (m, 1H), 6.55 (m, 1H), 6.45 (m, 1H), 6.27 (m, 1H), 5.80(m, 1H), 3.81 (s, 3H), 3.32 (m, 2H), 3.20-2.95 (m, 3H), 2.72 (s, 3H),1.95-1.80 (m, 3H), 1.60 (m, 1H); MS (ESI⁺): m/z = 516.1 [M + H]⁺. 116

¹H-NMR (300 MHz, DMSO-d₆) δ 10.30 (s, 1H), 9.27 (s, 1H), 8.28 (d, 1H),7.70 (m, 1H), 7.68 (m, 1H), 7.45 (dd, 1H), 7.35 (m, 2H), 7.18 (m, 1H),7.07 (m, 1H), 6.74 (m, 1H), 6.44 (dd, 1H), 6.27 (dd, 1H), 5.78 (dd, 1H),3.97 (t, 2H), 3.60 (s, 3H), 3.56 (m, 4H), 2.63 (t, 2H), 2.46 (m, 4H); MS(ESI⁺): m/z = 548.1 [M + H]⁺. 117

¹H-NMR (300 MHz, CDCl₃) δ 7.93 (m, 1H), 7.87 (d, 2H), 7.84 (s, 1H), 7.49(m, 2H), 7.41 (s, 1H), 7.29 (d, 1H), 7.14 (d, 1H), 7.02 (d, 1H), 6.37(m, 2H), 5.70 (m, 1H), 3.89 (s, 3H), 3.63 (t, 2H), 2.85 (t, 2H), 2.75(m, 4H), 1.90 (m, 4H); MS (ESI⁺): m/z = 558.9 [M + H]⁺. 118

¹H-NMR (300 MHz, DMSO-d₆) δ 10.37 (s, 1H), 9.79 (s, 1H), 8.35 (d, 1H),7.78 (m, 2H), 7.58 (m, 3H), 7.32 (m, 2H), 7.30 (d, 1H), 7.10 (d, 1H),6.44 (dd, 1H), 6.25 (d, 1H), 5.78 (d, 1H), 3.73 (s, 3H), 2.62 (m, 2H),2.16 (s, 3H), 2.03 (m, 2H), 1.78 (m, 2H), 1.50 (m, 2H); MS (ESI⁺): m/z =559.2 [M + H]⁺. 119

¹H-NMR (300 MHz, CDCl₃) δ 7.86 (d, 1H), 7.76 (s, 1H), 7.43 (m, 3H), 7.28(m, 1H), 6.99 (t, 2H), 6.76 (t, 1H), 6.40 (m, 2H), 5.73 (m, 1H), 3.71(m, 4H), 3.17 (s, 2H), 2.95 (m, 4H), 2.31 (s, 6H); MS (ESI⁺): m/z =575.9 [M + H]⁺. 120

¹H-NMR (300 MHz, DMSO-d₆) δ 10.36 (brs, 1H), 9.56 (brs, 1H), 8.33-8.31(d, 1H), 7.74 (m, 1H), 7.61-7.43 (m, 3H), 7.39- 7.38 (m, 1H), 7.27 (m,1H), 7.10-7.07 (m, 1H), 6.87 (m, 1H), 6.43-6.39 (m, 1H), 6.28-6.22 (m,1H), 5.79-5.75 (m, 1H), 3.24 (m, 4H), 2.98 (m, 4H), 2.93 (s, 3H); MS(ESI⁺): m/z = 591.06 [M + Na]⁺.

TABLE 1r Example Structure Analysis data 121

¹H-NMR (300 MHz, DMSO-d₆) δ 10.35 (brs, 1H), 9.55 (brs, 1H), 8.32-8.30(d, 1H), 7.79 (s, 1H), 7.60-7.43 (m, 3H), 7.39- 7.37 (d, 1H), 7.28-7.25(m, 1H), 7.09-7.06 (m, 1H), 6.89-6.82 (t, 1H), 6.47-6.38 (m, 1H),6.28-6.22 (m, 1H), 5.78-5.75 (m, 1H), 3.20-3.07 (m, 6H), 2.94 (m, 4H),1.26-1.21 (t, 3H). 122

¹H-NMR (300 MHz, DMSO-d₆) δ 9.53 (s, 1H), 8.30 (m, 1H), 7.73 (s, 1H),7.46 (m, 3H), 7.38 (d, 1H), 7.25 (m, 1H), 7.07 (d, 1H), 6.84 (d, 1H),6.41 (m, 1H), 6.26 (d, 1H), 3.63 (m, 4H), 2.86 (m, 4H); MS (ESI⁺): m/z =492.54 [M + H]⁺. 123

¹H-NMR (300 MHz, CDCl₃) δ 7.86 (d, 1H), 7.71 (s, 1H), 7.53 (m, 2H), 7.46(m, 2H), 7.29 (d, 1H), 7.14 (s, 1H), 7.05 (m, 1H), 6.93 (m, 1H), 6.78(t, 1H), 6.45 (dd, 1H), 6.25 (m, 1H), 5.79 (dd, 1H), 3.87 (m, 2H), 3.15(d, 2H), 2.39 (t, 2H), 1.23 (d, 6H); MS (ESI⁺): m/z = 520.2 [M + H]⁺ 124

¹H-NMR (300 MHz, CDCl₃) δ 7.86 (d, 1H), 7.79 (s, 1H), 7.67 (s, 1H), 7.42(m, 2H), 6.97 (m, 1H), 6.90 (s, 1H), 6.77 (d, 1H), 6.46 (t, 1H), 6.40(d, 1H), 6.29 (dd, 1H), 5.76 (d, 1H), 3.42 (d, 2H), 3.09 (m, 2H), 2.95(m, 2H), 2.06 (m, 6H); MS (ESI⁺): m/z = 559.2 [M + H]⁺. 125

¹H-NMR (300 MHz, CDCl₃) δ 7.87 (d, 1H), 7.78 (s, 1H), 7.48 (d, 1H), 7.25(d, 1H), 7.01 (d, 1H), 7.00 (d, 1H), 6.82 (t, 1H), 6.47 (m, 2H), 5.70(m, 1H), 4.42 (t, 1H), 4.37 (m, 1H), 3.33 (m, 4H), 2.58 (m, 4H), 2.35(m, 1H), 1.95 (m, 2H), 1.78 (m, 2H), 1.63 (m, 4H), 1.46 (m, 2H); MS(ESI⁺): m/z = 573.0 [M + H]⁺. 126

¹H-NMR (300 MHz, DMSO-d₆) δ 10.33 (s, 1H), 9.49 (s, 1H), 8.30 (d, 1H),7.71 (s, 1H), 7.59 (d, 1H), 7.46 (m, 2H), 7.20 (d, 1H), 7.05 (d, 1H),6.40 (dd, 1H), 6.26 (d, 1H), 5.77 (d, 1H), 3.68 (m, 4H), 3.19 (d, 2H),2.71 (m, 1H), 2.67 (m, 4H), 2.20 (m, 2H), 1.81 (m, 2H), 1.47 (m, 2H); MS(ESI⁺): m/z = 575.1 [M + H]⁺. 127

¹H-NMR (300 MHz, CDCl₃) δ 7.98 (s, 1H), 7.91 (d, 1H), 7.45 (m, 2H), 7.32(m, 2H), 7.04 (m, 3H), 6.43 (m, 2H), 5.78 (m, 1H), 3.04 (m, 2H), 2.78(m, 1H), 2.40 (s, 3H), 2.17 (m, 2H), 1.85 (m, 4H); MS (ESI⁺): m/z =504.2 [M + H]⁺.

TABLE 1s Example Structure Analysis data 128

¹H-NMR (300 MHz, CDCl₃) δ 7.86 (d, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.46(m, 3H), 7.30 (d, 1H), 7.19 (s, 1H), 7.02 (m, 2H), 6.91 (m, 1H), 6.45(m, 1H), 6.29 (m, 1H), 5.78 (m, 1H), 3.09 (m, 1H), 2.92 (m, 2H), 2.32(s, 3H), 1.95 (m, 2H), 1.77 (m, 3H), 1.44 (m, 1H); MS (ESI⁺): m/z =504.2 [M + H]⁺ 129

1H-NMR (300 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.27 (s, 1H), 8.27 (d, 1H),7.71 (s, 1H), 7.61 (d, 1H), 7.40 (m, 3H), 7.10 (m, 2H), 6.58 (m, 1H),6.50 (dd, 1H), 6.40 (d, 1H), 5.78 (d, 1H), 4.58 (d, 1H), 3.10 (m, 1H),2.72 (m, 2H), 2.17 (s, 3H), 2.00 (m, 2H), 1.80 (m, 2H), 1.44 (m, 2H); MS(ESI+): m/z = 519.2 [M + H]+. 130

¹H-NMR (300 MHz, DMSO-d₆) δ 10.34 (s, 1H), 9.25 (s, 1H), 8.27 (d, 1H),7.69 (s, 1H), 7.60 (d, 1H), 7.36 (m, 3H), 7.10 (m, 2H), 6.55 (m, 1H),6.40 (dd, 1H), 6.25 (d, 1H), 5.77 (d, 1H), 4.52 (d, 1H), 3.10 (m, 1H),2.66 (m, 2H), 2.15 (m, 2H), 1.83 (m, 2H), 1.35 (m, 2H), 0.96 (d, 6H); MS(ESI⁺): m/z = 547.2 [M + H]⁺. 131

¹H-NMR (300 MHz, CDCl₃) δ 7.84 (d, 1H), 7.63 (s, 1H), 7.46 (dd, 1H),7.37 (m, 2H), 7.24 (t, 1H), 7.02 (m, 1H), 6.83 (m, 2H), 6.43 (m, 1H),6.24 (m, 1H), 5.72 (dd, 1H), 4.11 (t, 2H), 3.73 (t, 2H), 3,43 (s, 3H);MS (ESI⁺): m/z = 481.0 [M + H]⁺. 132

¹H-NMR (300 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.51 (s, 1H), 8.31 (d, 1H),7.75 (s, 1H), 7.54 (m, 2H), 7.45 (m, 1H), 7.28 (m, 1H), 7.15 (m, 1H),6.90 (m, 1H), 6.40 (m, 1H), 6.21 (m, 1H), 5.70 (m, 1H), 4.00 (t, 2H),2.59 (t, 2H), 2.20 (s, 6H); MS (ESI⁺): m/z = 494.2 [M + H]⁺. 133

¹H-NMR (300 MHz, DMSO-d₆) δ 10.37 (s, 1H), 9.50 (s, 1H), 8.30 (d, 1H),7.74 (m, 1H), 7.56 (m, 2H), 7.44 (dd, 1H), 7.37 (d, 1H), 7.35 (d, 1H),7.15 (m, 1H), 6.95 (m, 1H), 6.43 (dd, 1H), 6.25 (dd, 1H), 5.65 (dd, 1H),4.02 (m, 2H), 2.80 (m, 2H), 2.56 (m, 4H), 0.97 (m, 6H); MS (ESI⁺): m/z =522.1 [M + H]⁺. 134

¹H-NMR (300 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.51 (s, 1H), 8..31 (m, 1H),7.74 (m, 1H), 7.57 (m, 2H), 7.45 (dd, 1H), 7.38 (d, 1H), 7.22 (m, 1H),7.08 (m, 1H), 6.94 (m, 1H), 6.43 (dd, 1H), 6.24 (dd, 1H), 5.76 (dd, 1H),4.02 (t, 2H), 2.64 (t, 2H), 2.49 (m, 4H), 2.30 (m, 4H), 2.14 (s, 3H); MS(ESI⁺): m/z = 549.2 [M + H]⁺.

TABLE 1t Example Structure Analysis data 135

¹H-NMR (300 MHz, CDCl₃) δ 7.86 (d, 1H), 7.78 (s, 1H), 7.51 (d, 1H), 7.41(m, 2H), 7.24 (m, 1H), 7.02 (m, 1H), 6.90 (d, 1H), 6.81 (t, 1H), 6.44(m, 1H), 6.27 (m, 1H), 5.77 (d, 1H), 4.11 (t, 2H), 3.75 (t, 4H), 2.80(t, 2H), 2.59 (t, 4H); MS (ESI⁺): m/z = 536.3 [M + H]⁺. 136

¹H-NMR (300 MHz, DMSO-d₆): δ 10.36 (brs, 1H), 9.54 (brs, 1H), 8.30-8.29(d, 1H), 7.73 (s, 1H), 7.58-7.55 (m, 2H), 7.46- 7.41 (t, 1H), 7.37-7.35(d, 1H), 7.22-7.20 (m, 1H), 7.08-7.05 (m, 1H), 6.97-6.91 (m, 1H),6.46-6.38 (m, 1H), 6.26-6.21 (m, 1H), 5.77-5.74 (m, 1H), 4.14 (m, 1H),2.66 (m, 2H), 2.22 (m, 5H), 1.84 (m, 2H), 1.62-1.59 (m, 2H); MS (ESI⁺):m/z = 520.2 [M + H]⁺. 137

¹H-NMR (300 MHz, DMSO-d₆) δ 10.32 (s, 1H), 9.55 (s, 1H), 8.30 (d, 1H),7.73 (m, 1H), 7.54 (m, 1H), 7.43 (m, 1H), 7.39 (m, 1H), 7.23(m, 2H),7.06 (m, H), 6.43(m, 1H), 6.21 (dd, 1H), 5.75 (dd, 1H), 3.58 (d, 1H),3.02 (m, 1H), 2.49 (m, 2H), 2.11 (s, 3H), 1.84 (t, 2H), 1.67 (d, 2H),1.35 (m, 2H); MS (ESI⁺): m/z = 537.2 [M + H]⁺. 138

¹H-NMR (300 MHz, CDCl₃) δ 7.85 (d, 1H), 768 (dd, 2H), 7.47 (m 1H), 7.39(m, 1H), 7.20 (dd, 1H), 7.06 (d, 1H), 6.88 (s, 2H), 6.42 (d, 1H), 6.29(dd, 1H), 5.78 (d, 1H), 3.28 (m, 2H), 2.80 (m, 2H), 2.01 (m, 2H), 1.98(m, 5H), 1.25 (m, 3H); MS (ESI⁺): m/z = 575 [M + H]⁺. 139

¹H-NMR (300 MHz, DMSO-d₆) δ 10.6 (brs, 1H), 10.4 (s, 1H), 9.57 (s, 1H),8.33 (d, 1H), 7.74 (s, 1H), 7.65 (d, 1H), 7.38 (m, 1H), 7.09 (d, 1H),6.95 (d, 1H), 6.42 (dd, 1H), 6.23 (d, 1H), 5.79 (d, 1H), 3.99 (d, 2H),3.78 (m, 2H), 3.48 (d, 2H), 3.25 (d, 2H), 2.63 (m, 2H), 2.16 (m, 2H),1.82 (m, 2H); MS (ESI⁺): m/z = 591 [M + H]⁺. 140

¹H-NMR (300 MHz, CDCl₃) δ 7.85 (m, 2H), 7.42 (m, 2H), 7.37 (m, 2H), 7.33(m, 2H), 7.03 (m, 4H), 6.41 (m, 1H), 6.33 (m, 1H), 5.73 (m, 1H), 3.73(m, 1H), 3.08 (m, 2H), 2.23 (m, 2H), 1.82 (m, 4H); MS (ESI⁺): m/z =519.1 [M + H]⁺. 141

¹H-NMR (300 MHz, CD₃OD) δ 8.04 (d, 1H), 7.68 (d, 1H), 7.57 (m, 1H), 7.49(d, 1H), 7.42 (t, 3H), 7.24-7.16 (m, 2H), 7.03- 7.01 (m, 1H), 6.59 (d,1H), 6.42-6.38 (m, 2H), 5.79-5.75 (m, 1H), 3.32-3.30 (m, 1H), 2.86-2.82(m, 2H), 2.31-2.22 (m, 5H), 2.09-1.99 (m, 2H), 1.56-1.45 (m, 2H); MS(ESI⁺): m/z = 535.16 [M + H]⁺.

TABLE 1u Example Structure Analysis data 142

¹H-NMR (300 MHz, DMSO-D₆) δ 10.24 (s, 1H), 8.40 (m, 2H), 7.61 (s, 1H),7.45 (m, 1H), 7.26 (m, 4H), 6.87 (m, 1H), 6.39 (dd, 1H), 6.23 (d, 1H),5.75 (d, 1H), 3.56 (m, 1H), 2.73 (m, 2H), 2.15 (s, 3H), 1.95 (m, 2H),1.77 (m, 2H), 1.55 (m, 2H); MS (ESI⁺): m/z = 563.2 [M + H]⁺. 143

¹H-NMR (300 MHz, CDCl₃) δ 8.04 (m, 1H), 7.89 (d, 1H), 7.45 (m, 2H), 7.36(m, 1H), 7.27 (d, 1H), 7.15 (m, 1H), 7.03 (dd, 1H), 6.98 (dd, 1H), 6.43(d, 1H), 6.27 (d, 1H), 5.75 (d, 1H), 3.12 (s, 3H), 2.85 (s, 3H); MS(ESI⁺): m/z = 494 [M + H]⁺. 144

¹H-NMR (300 MHz, CDCl₃) δ 8.32 (d, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.60(s, 1H), 7.40 (m, 1H), 7.30 (m, 1H), 7.22 (d, 1H), 6.98 (m, 2H), 6.45(d, 1H), 6.30 (dd, 1H), 5.79 (d, 1H), 4.11 (m, 2H), 3.95 (m, 2H), 3.41(m, 2H), 3.21 (m, 2H), 1.24 (t, 2H), 1.25 (s, 3H); MS (ESI⁺): m/z =627.7 [M + H]⁺. 145

¹H-NMR (300 MHz, DMSO-d₆) δ 10.40 (s. III). 9.61 (s, 1H), 8.33 (d, 1H),7.90 (d, 1H), 7.78 (s, 1H), 7.57 (m, 1H), 7.45 (m, 4H), 7.07 (m, 2H),6.41 (dd, 1H), 6.25 (d, 1H), 5.76 (d, 1H), 3.64 (m, 1H), 2.74 (m, 2H),2.15 (s, 6H), 1.94 (m, 2H), 1.73 (m, 2H), 1.49 (m, 2H); MS (ESI⁺): m/z =543.2 [M + H]⁺. 146

¹H-NMR (300 MHz, DMSO-d₆) δ 10.33 (s, 1H), 9.24 (s, 1H), 8.28 (d, 1H),8.26 (m, 1H), 7.69 (m, 1H), 7.59 (m, 1H), 7.45 (m, 1H), 7.34 (m, 1H),7.32 (m, 1H), 7.08 (m, 1H), 6.63 (m, 1H), 6.33 (m, 1H), 6.28 (dd, 1H),5.77 (dd, 1H), 3.62 (m, 4H), 2.69 (m, 1H), 2.48 (m, 4H), 1.07 (d, 6H);MS (ESI⁺): m/z = 516.20 [M + H]⁺. 147

¹H-NMR (300 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.22 (s, 1H), 8.32 (m, 1H),8.26 (m, 1H), 7.78 (m, 1H), 7.68 (m, 1H), 7.58 (m, 1H), 7.41 (m, 2H),7.31 (m, H), 7.05 (m, 1H), 6.64 (m, 1H), 6.42 (m, 3H), 6.24 (dd, 1H),5.76 (dd, 1H), 3.33 (m, 2H), 2.49~2.37 (m, 10H), 2.13 (s, 6H); MS(ESI⁺): m/z = 515.2 [M + H]⁺. 148

¹H-NMR (300 MHz, DMSO-d₆) δ 10.33 (s, 1H), 9.30 (s, 1H), 8.27 (m, 1H),8.25 (m, 1H), 7.75 (m, 1H), 7.68 (m, 1H), 7.58 (m, 1H), 7.43 (m, 1H),7.31 (m, 1H), 7.04 (m, 1H), 6.60 (m, 1H), 6.43 (m, 1H), 6.28 (dd, 1H),5.76 (dd, 1H), 3.31 (m, 5H), 2.76 (m, 2H), 2.50 (m, 4H), 2.12 (s, 3H),1.74 (m, 4H), 1.38 (m, 2H); MS (ESI⁺): m/z = 571.30 [M + H]⁺.

TABLE 1v Example Structure Analysis data 149

¹H-NMR (300 MHz, DMSO-d₆) δ 10.33 (s, 1H), 9.24 (s, 1H), 8.28 (d, 1H),8.26 (m, 1H), 7.69 (m, 1H), 7.59 (m, 1H), 7.45 (m, 1H), 7.34 (m, 1H),7.32 (m, 1H), 7.08 (m, 1H), 6.63 (m, 1H), 6.33 (m, 1H), 6.28 (dd, 1H),5.77 (dd, 1H), 3.65 (m, 4H), 3.57 (m, 4H); MS (ESI⁺): m/z = 474.2 [M +H]⁺. 150

¹H-NMR (300 MHz, DMSO-d₆) δ 10.35 (s, 1H), 9.18 (s, 1H), 8.28 (m, 1H),8.25(m, 1H), 7.73 (m, 1H), 7.59 (m, 1H), 7.45 (m, 1H), 7.40 (m, 1H),7.30 (m, 1H), 7.03 (m, 1H), 6.64 (m, 1H), 6.43 (m, 1H), 6.28 (dd, 1H),5.76 (dd, 1H), 3.32 (m, 2H), 2.63 (m, 2H), 2.23 (m, 1H), 2.15 (s, 6H),1.74 (m, 2H), 1.29 (m, 2H); MS (ESI⁺): m/z = 516.2 [M + H]⁺. 151

¹H-NMR (300 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.24 (s, 1H), 8.31 (d, 1H),8.25 (m, 1H), 7.82 (m, 1H), 7.79 (m, 1H), 7.55 (m, 1H), 7.40 (m, 1H),7.33 (m, 1H), 7.05 (m, 1H), 6.63 (m, 1H), 6.33 (m, 1H), 6.28 (dd, 1H),5.77 (dd, 1H), 4.01 (m, 2H), 3.16 (m, 2H), 2.78 (m, 2H), 2.51 (m, 2H),2.12 (m, 1H), 1.88 (m, 2H), 1.67 (m, 4H), 1.44 (m, 2H); MS (ESI⁺): m/z =542.2 [M + H]⁺. 152

¹H-NMR (300 MHz, DMSO-d₆) δ 10.33 (s, 1H), 9.18 (s, 1H), 8.36 (m, 1H),8.25 (m, 1H), 7.73 (m, 1H), 7.69 (m, 1H), 7.47 (m, 1H), 7.41 (m, 1H),7.31 (m, 1H), 7.04 (m, 1H), 6.61 (m, 1H), 6.45 (m, 1H), 6.29 (dd, 1H),5.76 (dd, 1H), 4.08 (m, 2H), 3.43 (m, 1H), 2.65 (m, 2H), 2.49 (m, 4H),1.72 (m, 2H), 1.39 (m, 4H), 1.36 (m, 4H); MS (ESI⁺): m/z = 556.2 [M +H]⁺. 153

¹H-NMR (300 MHz, DMSO-d₆) δ 10.33(s, 1H), 9.24(s, 1H), 8.31 (d, 1H),8.26 (m, 1H), 7.82 (m, 1H), 7.79 (m, 1H), 7.58 (m, 1H), 7.42 (m, 1H),7.32 (m, 1H), 7.05 (m, 1H), 6.63 (m, 1H), 6.33 (m, 1H), 6.28 (dd, 1H),5.76 (dd, 1H), 3.67 (m, 4H), 3.28 (m, 4H); MS (ESI⁺): m/z = 516.2 [M +H]⁺. 154

¹H-NMR (300 MHz, DMSO-d₆) δ 10.34 (s, 1H), 9.08 (s, 1H), 8.35 (d, 1H),8.23 (m, 1H), 7.65 (d, 1H), 7.57 (m, 1H), 7.42 (m, 2H), 7.28 (d, 1H),7.04 (m, 1H), 6.42 (m, 2H), 6.28 (m, 2H), 6.02 (d, 1H), 5.74 (dd, 1H),2.67 (m, 4H), 2.16 (m, 2H), 1.84 (m, 2H), 1.33 (m, 2H), 0.97 (m, 6H); MS(ESI⁺): m/z = 530.2 [M + H]⁺. 155

¹H-NMR (300 MHz, DMSO-d₆) δ 10.39 (s, 1H), 10.05 (s, 1H), 8.86 (s, 1H),8.37 (d, 1H), 8.31 (d, 1H), 7.80 (s, 1H), 7.45~7.63 (m, 4H), 7.10 (d,1H), 6.39 (m, 1H), 6.22 (dd, 1H), 5.75 (dd, 1H); MS (ESI⁺): m/z = 452.1[M + H]⁺. 156

¹H-NMR (300 MHz, DMSO-d₆): δ 10.38 (brs, 1H), 9.33 (s, 1H), 8.31-8.29(d, 1H), 7.88 (s, 1H), 7.71 (s, 1H), 7.65-7.61 (m, 2H), 7.48-7.43 (t,1H), 7.36-7.34 (d, 1H), 7.09-7.02 (m, 2H), 6.48-6.41 (m, 1H), 6.27-6.21(m, 1H), 5.78-5.75 (m, 1H), 4.52- 4.41 (m, 1H), 3.53-3.44 (m, 2H), 3.03(m, 4H), 2.66-2.48 (m, 6H); MS (ESI⁺): m/z = 518 [M + H]⁺.

Example 157 Preparation ofN-(3-(2-(4-(4-methyl-4-oxy-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidine-4-yloxy)-phenyl)-acrylamide

The compound (100 mg, 0.21 mmol) obtained in Example 1 was dissolved indichloromethane (2 mL), and m-chloroperbenzoic acid (71 mg, 0.42 mmol)was added thereto, followed by stirring at 45° C. for 12 hours. Afterthe reaction was complete, the reaction mixture was diluted withdichloromethane and washed with sat. NaHCO₃ aqueous solution. Theorganic layer was dried with anhydrous sodium sulfate and then filteredand distilled under a reduced pressure, and the residue was separated bycolumn chromatography (chloroform saturated with ammonia:methanol=4:1(volume ratio)) to obtain the title compound (yield: 25 mg, 40%).

¹H-NMR (300 MHz, DMSO-d₆) δ 10.38 (s, NH), 9.27 (s, NH), 8.28 (d, 1H),7.74 (s, 1H), 7.60 (d, 1H), 7.46 (m, 3H), 7.33 (d, 1H), 7.05 (d, 1H),6.78 (d, 2H), 6.43 (m, 1H), 6.28 (m, 1H), 5.76 (m, 1H), 3.57 (m, 4H),2.98 (s, 3H), 2.95 (m, 2H), 2.50 (m, 2H);

MS (ESI⁺): m/z=503.1 [M+H]⁺.

Example 158 Preparation ofN-(3-(2-(4-(piperazin-1-yl)phenylamino)-thieno[3,2-d]pyrimidine-4-yloxy)-phenyl)-acrylamide

Step 1) Preparation of4-(4-(4-(3-acryloylamino-phenoxy)-thieno[3,2-d]pyrimidine-2-ylamino)-phenyl)-piperazin-1-carboxylicacid tert-butyl ester

The procedure of Step 4 of Example 1 was repeated except for usingtert-butyl 4-(4-aminophenyl)piperazin-1-carboxylate instead of4-(4-methylpiperazin-1-yl)benzeneamine to obtain the title compound(yield: 610 mg, 91%).

¹H-NMR (300 MHz, CDCl₃) δ 7.82-7.80 (m, 1H), 7.59-7.52 (m, 3H),7.43-7.34 (m, 3H), 7.06-7.03 (m, 1H), 6.92 (s, 1H), 6.80-6.77 (m, 2H),6.47-6.41 (m, 1H), 6.27-6.24 (m, 1H), 5.79-5.75 (m, 1H), 3.57 (m, 4H),3.02-2.99 (m, 4H), 1.48 (s, 9H).

Step 2) Preparation ofN-(3-(2-(4-(piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidine-4-yloxy)-phenyl)-acrylamide

The compound (600 mg, 1.05 mmol) obtained in Step 1 was dissolved indichloromethane (10 mL), and trifluoroacetic acid (1.62 mL, 21.0 mmol)was added thereto, followed by stirring at room temperature for 1 hour.After the reaction was complete, the reaction mixture was distilledunder a reduced pressure to remove solvent, alkalify (pH 8) with sat.NaHCO₃ aqueous solution, and extracted with chloroform 2 times. Theorganic layer was separated, washed with water and sat. brine, driedwith anhydrous sodium sulfate, and then filtered and distilled under areduced pressure. The residue was separated by column chromatography(chloroform:methanol=10:1 (volume ratio)) to obtain the title compound(yield: 316 mg, 72%).

¹H-NMR (300 MHz, CDCl₃) δ 10.28 (brs, 1H), 9.15 (brs, 1H), 8.26-8.24 (m,1H), 7.68 (s, 1H), 7.62-7.59 (m, 1H), 7.50-7.41 (m, 1H), 7.31-7.29 (m,1H), 7.06-7.00 (m, 1H), 6.74-6.71 (m, 2H), 6.44-6.38 (m, 1H), 6.27-6.21(m, 1H), 5.78-5.74 (m, 1H), 3.31 (m, 4H), 3.04-2.96 (m, 4H);

MS (ESI⁺): m/z=473.4 [M+H]⁺.

The procedure of Example 158 was repeated except for using tert-butyl4-(4-amino-2-chlorophenyl)piperazin-1-carboxylate or[1-(4-aminophenyl)cyclopropyl]carbamic acid tert-butyl ester instead oftert-butyl 4-(4-aminophenyl)piperazin-1-carboxylate in Step 4, toprepare the compounds of Examples 159 and 160 which are shown in Table 2below.

TABLE 2 Example Structure Analysis data 159

¹H-NMR (300 MHz, DMSO-d₆) δ 9.54 (brs, 1H), 8.30 (d, 1H), 7.86-7.71 (m,2H), 7.59 (d, 1H), 7.47-7.41 (m, 2H), 7.35 (d, 1H), 7.05 (m, 1H), 6.92(m, 1H), 6.39-6.50 (m, 1H), 6.27-6.16 (m, 1H), 5.77-5.74 (m, 1H),2.99-2.89 (m, 8H); MS (ESI⁺): m/z = 507.13 [M + H]⁺. 160

¹H-NMR (300 MHz, CDCl₃) δ 7.85 (d, 1H), 7.66 (m, 2H), 7.55 (m, 1H), 7.42(m, 2H), 7.15 (d, 2H), 7.11 (d, 1H), 7.01 (s, 1H), 6.42 (d, 1H), 6.25(dd, 1H), 5.79 (d, 1H), 0.96 (m, 2H), 0.89 (m, 2H); MS (ESI⁺): m/z = 444[M + H]⁺.

Example 161 Preparation of(Z)-3-chloro-N-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidine-4-yloxy)phenyl)acrylamide

The compound (50 mg, 0.12 mmol) obtained in Step 5 of Example 1 wasdissolved in pyridine (1.5 mL), and cis-3-chloroacrylic acid (18 mg,0.17 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloric acid salt (44 mg, 0.23 mmol) were added thereto, followedby stirring at room temperature for 1 hour. After the reaction wascomplete, the reaction mixture was diluted with a mixed solvent(chloroform:2-propanol=3:1 (volume ratio)) and washed with sat. brine.The organic layer was dried with anhydrous sodium sulfate and thenfiltered and distilled under a reduced pressure. The residue wasseparated by column chromatography (dichloromethane:methanol=6:1 (volumeratio)) to obtain the title compound (yield: 15 mg, 24%).

¹H-NMR (300 MHz, CDCl₃) δ 8.24 (s, 1H), 7.82 (d, 1H), 7.62 (s, 1H), 7.57(d, 1H), 7.44 (d, 1H), 7.39 (d, 1H), 7.35 (s, 1H), 7.26 (d, 1H), 7.08(m, 1H), 6.98 (s, 1H), 6.81 (d, 2H), 6.62 (d, 1H), 6.34 (d, 1H), 3.13(t, 4H), 2.59 (t, 4H), 2.36 (s, 3H);

MS (ESI⁺): m/z=521.4 [M+H]⁺.

The procedure of Example 161 was repeated except for usingtrans-3-chloroacrylic acid and (E)-4-(dimethylamino)-2-butenoic acid toprepare the compounds of Examples 162 and 163 which are shown in Table 3below.

TABLE 3 Example Structure Analysis data 162

¹H-NMR (300 MHz, CDCl₃) δ 7.82 (d, 1H), 7.62 (m, 2H), 7.55 (d, 1H), 7.42(s, 1H), 7.41 (d, 1H), 7.35 (d, 2H), 7.25 (d, 1H), 7.08 (d, 1H), 6.92(s, 1H), 6.81 (d, 2H), 6.40 (d, 1H), 3.14 (t, 4H), 2.61 (t, 4H), 2.38(s, 3H); MS (ESI⁺): m/z = 521.3 [M + H]⁺. 163

¹H-NMR (300 MHz, CDCl₃) δ 7.80 (d, 1H), 7.56 (m, 2H), 7.41 (d, 2H), 7.36(d, 2H), 7.25 (d, 1H), 6.99 (d, 1H), 6.95 (m, 1H), 6.90 (s, 1H), 6.80(d, 2H), 6.07 (m, 1H), 3.12 (t, 4H), 3.10 (d, 2H), 2.59 (t, 4H), 2.36(s, 3H) 2.27 (s, 6H); MS (ESI⁺): m/z = 544.2 [M + H]⁺.

Example 164 Preparation ofN-(4-methyl-3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide

A similar procedure as the procedure of Example 1 was carried out exceptfor using 2-methyl-5-nitrophenol (25 mmol), instead of 3-nitrophenol instep 3), to obtain the title compound (30 mg, final yield: 34%).

¹H-NMR (300 MHz, DMSO-d₆) δ 10.27 (s, 1H), 9.21 (s, 1H), 8.25 (d, 1H),7.62 (s, 1H), 7.55 (d, 1H), 7.33 (m, 4H), 6.69 (m, 2H), 6.39 (m, 1H),6.25 (m, 1H), 5.75 (d, 1H), 2.96 (m, 4H), 2.42 (m, 4H), 2.20 (s, 3H),2.07 (s, 3H);

MS (ESI⁺): m/z=501.2 [M+H]⁺.

A similar procedure as the procedure of Example 164 was carried outexcept for using 2-fluoro-5-nitrophenol and 2-methoxy-5-nitrophenol, toobtain compounds of Example 165 and Example 166, respectively.

TABLE 4 Example Structure Analysis data 165

¹H-NMR (300 MHz, DMSO-d₆) δ 10.40 (s, 1H), 9.30 (s, 1H), 8.31 (d, 1H),7.83 (m, 1H), 7.64 (m, 1H), 7.46 (dd, 1H), 7.38 (m, 2H), 7.34 (d, 1H),6.71 (m, 1H), 6.41 (dd, 1H), 6.27 (dd, 1H), 5.79 (dd, 1H), 3.00 (m, 4H),2.44 (m, 4H), 2.22 (s, 3H); MS (ESI⁺): m/z = 505.2 [M + H]⁺. 166

¹H-NMR (300 MHz, DMSO-d₆) δ 10.18 (s, 1H), 9.20 (s, 1H), 8.24 (d, 1H),7.63 (m, 2H), 7.35 (d, 2H), 7.29 (d, 1H), 7.20 (d, 1H), 6.69 (d, 2H),6.36 (dd, 1H), 6.22 (dd, 1H), 5.75 (dd, 1H), 3.68 (s, 3H), 2.98 (m, 4H),2.44 (m, 4H), 2.20 (s, 3H); MS (ESI⁺): m/z = 517.2 [M + H]⁺.

Example 167 Preparation ofN-(3-(2-(5-(4-methylpiperazin-1-yl)piridin-2-ylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide

Step 1) Preparation ofN-(5-(4-methylpiperazin-1-yl)piridin-2-yl)-4-(3-nitrophenoxy)thieno[3,2-d]pyrimidin-2-amine

0.6 g (1.94 mmol) of the compound obtained in Step 3 of Example 1 and0.75 g (3.88 mmol) of 5-(4-methylpiperazin-1-yl)piridin-2-amine weredissolved in 8 ml of 1,4-dioxane, and 178 mg (0.2 mmol) oftris(dibenzylideneacetone)dipalladium(O) and 122 mg (0.2 mmol) of2,2′-bis(diphenylphosphino)-1,1′-binaphthy were added thereto, andstirred for 5 minutes at room temperature. 1.27 g (3.88 mmol) of cesiumcarbonate was added thereto, and stirred for 3 hours at 100° C. Upon thecompletion of the reaction, the resulting mixture was cooled to roomtemperature and filtered over a short bed of Celite filter, and dilutedwith dichloromethane and washed with water. The organic layer wasseparated, dried over anhydrous Na₂SO₄, and filtered and distilled undera reduced pressure. The resulting residue was separated by columnchromatography (dichloromethane:methanol (20:1, v/v)) to obtain 630 mgof the title compound (yield: 70%).

¹H-NMR (300 MHz, DMSO-d₆) δ 9.42 (s, 1H), 8.33 (m, 2H), 8.20 (m, 1H),7.91 (m, 2H), 7.80 (m, 1H), 7.59 (m, 1H), 7.39 (m, 1H), 7.05 (m, 1H),3.05 (m, 4H), 2.49 (m, 4H), 2.22 (s, 3H).

Step 2) Preparation ofN-(3-(2-(5-(4-methylpiperazin-1-yl)piridin-2-ylamino)thieno[3,2-d]pyrimidin-4-yloxy)phenyl)acrylamide

The procedure of step 5) and 6) of Example 1 were repeated sequentiallyexcept for using the compound obtained in the step 1) (1.35 mmol),instead ofN-(4-(4-methylpiperazin-1-yl)phenyl)-4-(3-nitrophenoxy)thieno[3,2-d]pyrimidin-2-amine,to obtain 50 mg of the title compound (final yield: 34%).

¹H-NMR (300 MHz, DMSO-d₆) δ 10.50 (s, 1H), 9.37 (s, 1H), 8.10 (d, 1H),7.90 (d, 1H), 7.72 (m, 1H), 7.64 (m, 2H), 7.47 (dd, 1H), 7.37 (d, 1H),7.09 (m, 2H), 6.42 (dd, 1H), 6.25 (dd, 1H), 5.77 (dd, 1H), 3.01 (m, 4H),2.42 (m, 4H), 2.22 (s, 3H);

MS (ESI⁺): m/z=488.3[M+H]⁺.

The procedure of Example 167 or a similar procedure was repeated exceptfor using various amine derivatives of Z—NH₂ (Z has the same meaning asdefined in the present invention), instead of5-(4-methylpiperazin-1-yl)piridin-2-amine in step 1) of Example 167, toobtain the title compounds of Examples 168 to 205 as shown in Tables 5ato 5f.

TABLE 5a Example Structure Analysis data 168

¹H-NMR (300 MHz, CDCl₃) δ 7.94 (d, 1H), 7.91 (d, 1H), 7.85 (d, 1H), 7.63(s, 1H), 7.60 (m, 1H), 7.55 (s, 1H), 7.43 (d, 1H), 7.41 (d, 1H), 7.31(d, 1H), 7.10 (dd, 1H), 7.02 (dd, 1H), 6.45 (dd, 1H), 6.23 (m, 1H), 5.79(dd, 1H), 3.14 (t, 4H), 2.62 (t, 4H), 2.48 (q, 2H), 1.14 (t, 3H); MS(ESI⁺): m/z = 502.4 [M + H]⁺. 169

¹H-NMR (300 MHz, DMSO-d₆) δ 10.35 (s, 1H), 9.62 (s, 1H), 8.77 (s, 1H),8.30 (d, 1H), 7.99 (m, 1H), 7.71 (m, 1H), 7.54 (m, 1H), 7.37 (m, 2H),7.06 (m, 2H), 6.41 (m, 1H), 6.21 (dd, 1H), 5.74 (dd, 1H), 3.45 (m, 2H),2.32 (m, 8H), 2.12 (s, 3H); MS (ESI⁺): m/z = 502.2 [M + H]⁺. 170

¹H-NMR (300 MHz, DMSO-d₆) δ 10.35 (brs, 1H), 9.71 (brs, 1H), 8.33-8.31(m, 1H), 7.85-7.84 (m, 1H), 7.74 (s, 1H), 7.56- 7.37 (m, 3H), 7.17-7.11(t, 1H), 7.08-7.05 (m, 1H), 6.45-6.36 (m, 1H), 6.25-6.20 (m, 1H),5.77-5.73 (m, 1H); MS (ESI⁺): m/z = 441.3 [M + H]⁺. 171

¹H-NMR (300 MHz, DMSO-d₆) δ 10.35 (s, 1H), 9.12 (s, 1H), 8.25 (d, 1H),7.63 (m, 2H), 7.42 (m, 4H), 7.06 (m, 1H), 6.50 (m, 3H), 6.24 (m, 1H),5.77 (m, 1H), 2.78 (s, 3H); MS (ESI⁺): m/z = 432.3 [M + H]⁺. 172

¹H-NMR (300 MHz, DMSO-d₆) δ 10.60 (s, 1H), 9.45 (s, 1H), 8.29 (s, 2H),7.70 (m, 1H), 7.58 (m, 1H), 7.46 (m, 3H), 7.34 (m, 1H), 7.17 (m, 2H),7.09 (m, 1H), 6.40 (dd, 1H), 6.26 (dd, 1H), 5.77 (dd, 1H), 3.42 (m, 4H),2.29 (m, 4H), 2.17 (s, 3H); MS (ESI⁺): m/z = 530.2 [M + H]⁺. 173

¹H-NMR (300 MHz, DMSO-d₆) δ 10.34 (s, 1H), 9.46 (s, 1H), 8.29 (d, 1H),7.72 (s, 1H), 7.60 (m, 1H), 7.48 (m, 3H), 7.35 (d, 1H), 7.07 (d, 1H),6.99 (d, 2H), 6.40 (m, 1H), 6.23 (m, 1H), 5.75 (m, 1H), 3.22 (s, 2H),2.06 (s, 6H); MS (ESI⁺): m/z = 446.4 [M + H]⁺. 174

¹H-NMR (300 MHz, CDCl₃) δ 7.87-7.83 (m, 2H), 7.48 (m, 1H), 7.42-7.37 (t,1H), 7.33-7.30 (m, 2H), 7.20-7.17 (m, 2H), 7.10 (brs, 1H), 7.02-6.99 (m,1H), 6.43-6.37 (m, 2H), 5.73-5.69 (m, 1H), 3.48 (s, 2H), 2.71-2.64 (m,4H), 1.08-1.03 (t, 6H); MS (ESI⁺): m/z = 473.96 [M + H]⁺.

TABLE 5b Example Structure Analysis data 175

¹H-NMR (300 MHz, CDCl₃) δ 8.06 (s, 1H), 7.87 (d, 1H), 7.44 (s, 1H), 7.36(m, 1H), 7.33 (m, 3H), 7.04 (m, 3H), 7.02 (s, 1H), 6.39 (d, 1H), 6.27(dd, 1H), 5.72 (d, 1H), 3.48 (s, 2H), 3.18 (m, 4H), 2.03 (m, 2H); MS(ESI⁺): m/z = 458.17 [M + H]⁺. 176

¹H-NMR (300 MHz, CDCl₃) δ 9.75 (brs, 1H), 8.37 (s, 1H), 7.87 (d, 2H),7.46 (m, 2H), 7.37 (d, 1H), 7.21 (m, 3H), 6.96 (d, 1H), 6.63 (dd, 1H),6.36 (dd, 1H), 5.67 (d, 1H), 3.85 (s, 2H), 3.02 (m, 4H), 2.17 (m, 4H);MS (ESI⁺): m/z = 472.2 [M + H]⁺. 177

¹H-NMR (300 MHz, CD₃OD) δ 8.07 (d, 1H), 7.72 (S, 1H), 7.60 (d, 1H),7.48-7.42 (m, 3H), 7.28 (d, 1H), 7.10-7.03 (m, 3H), 6.43-6.38 (m, 2H),5.80-5.76 (m, 1H), 3.59-3.47 (m, 2H), 2.91-2.74 (m, 3H), 2.50-2.47 (m,6H), 2.30-2.22 (m, 7H), 2.01- 1.99 (m, 1H), 1.72-1.71 (m, 1H); MS(ESI⁺): m/z = 515.22 [M + H]⁺. 178

¹H-NMR (300 MHz, CDCl₃) δ 8.03 (s, 1H), 7.80 (d, 1H), 7.78-7.28 (m, 4H),7.19 (s, 2H), 6.88 (d, 1H), 6.57 (dd, 1H), 6.27 (d, 1H), 5.59 (d, 1H),3.78 (s, 2H), 2.75 (t, 4H), 1.82 (t, 4H), 1.53-1.51 (m, 2H); MS (ESI⁺):m/z = 486.3 [M + H]⁺. 179

¹H-NMR (300 MHz, DMSO-d₆) δ 10.42 (brs, 1H), 9.61 (brs, 1H), 8.32 (d,1H), 7.74-7.08 (m, 9H), 6.45-6.40 (d, 1H), 6.26 (dd, 1H), 5.77 (dd, 1H),3.74-3.62 (m, 2H), 2.75-2.71 (m, 2H), 2.13-2.06 (m, 2H), 1.88-1.85 (m,2H), 1.62-1.52 (m, 3H); MS (ESI⁺): m/z = 502.18 [M + H]⁺. 180

¹H-NMR (300 MHz, DMSO-d₆) δ 10.33 (brs, 1H), 9.45 (brs, 1H), 8.28 (d,1H), 7.71 (S, 1H), 7.60 (d, 1H), 7.50-7.42 (m, 3H), 7.34 (d, 1H),7.08-7.05 (m, 1H), 6.98 (d, 2H), 6.46-6.37 (m, 1H), 6.27-6.21 (m, 1H),5.75 (dd, 1H), 3.33-3.21 (m, 2H), 2.76- 2.72 (m, 2H), 2.11 (s, 6H),1.99-1.96 (m, 1H), 1.84-1.77 (m, 2H), 1.66-1.62 (m, 2H), 1.28-1.04 (m,2H); MS (ESI⁺): m/z = 529.23 [M + H]⁺. 181

¹H-NMR (300 MHz, DMSO-d₆) δ 10.36 (s, NH), 9.47 (s, NH), 8.32 (d, !H),7.73 (s, 1H), 7.64 (d, 1H), 7.52 (m, 3H), 7.38 (d, !H), 7.11 (d, 1H),7.02 (d, 1H), 6.43 (dd, 1H), 6.24 (d, 1H), 5.76 (d, 1H), 3.59 (s, 1H),3.47 (m, 1H), 3.31 (m, 4H), 2.76 (m, 2H), 2.43 (m, 4H), 1.86 (m, 2H),1.79 (m, 2H), 1.36 (m, 2H); MS (ESI⁺): m/z = 571.2 [M + H]⁺.

TABLE 5c Example Structure Analysis data 182

¹H-NMR (300 MHz, DMSO-d₆) δ 7.97 (d, 1H), 7.55 (m, 1H), 7.45 (m, 1H),7.30 (m, 3H), 7.25 (d, 1H), 6.95 (m, 3H), 6.29 (m, 2H), 6.02 (m, 1H),3.41 (s, 2H), 2.55 (m, 8H), 2.36 (s, 3H); MS (ESI⁺): m/z = 501.11 [M +H]⁺. 183

¹H-NMR (300 MHz, CD₃OD) δ 8.08 (d, 1H), 8.02 (m, 1H), 7.61 (m, 1H), 7.46(m, 3H), 7.27 (d, 1H), 7.08 (m, 3H), 6.46 (d, 1H), 6.39 (d, 1H), 5.78(m, 1H), 3.47 (s, 2H), 2.56 (br, 8H), 2.46 (q, 2H), 1.13 (t, 3H); MS(ESI⁺): m/z = 515.4 [M + H]⁺. 184

¹H-NMR (300 MHz, CDCl₃) δ 8.10 (s, 1H), 7.82 (d, 1H), 7.69 (s, 1H), 7.47(m, 1H), 7.40 (s, 1H), 7.37 (d, 1H), 7.34 (d, 1H), 7.26 (d, 1H), 7.10(m, 3H), 7.02 (d, 1H), 6.42 (m, 1H), 6.25 (m, 1H), 5.73 (m, 1H), 3.29(q, 1H), 2.46 (m, 8H), 2.39 (q, 2H), 1.34 (d, 3H), 1.06 (t, 3H); MS(ESI⁺): m/z = 529.3 [M + H]⁺. 185

¹H-NMR (300 MHz, CDCl₃) δ 7.85-7.83 (d, 1H), 7.50- 7.22 (m, 6H),7.14-7.11 (m, 2H), 7.06-7.01 (m, 2H), 6.46- 6.41 (m, 2H), 6.30-6.21 (m,1H), 5.78-5.75 (m, 1H), 3.46 (s, 2H), 2.51 (m, 6H), 2.28 (d, 2H), 1.76(m, 2H), 0.88-0.83 (m, 1H), 0.53-0.47 (m, 2H), 0.12-0.07 (m, 2H); MS(ESI⁺): m/z = 541.4 [M + H]⁺. 186

¹H-NMR (300 MHz, CDCl₃) δ 7.84 (d, 1H), 7.61 (m, 2H), 7.49 (m, 1H),7.43(d, 3H), 7.19 (d, 2H), 6.97 (s, 1H), 6.45 (d, 1H), 6.26 (d, 1H), 5.78(d, 1H), 3.48 (d, 2H), 3.43 (s, 1H), 2.89 (d, 2H), 2.57 (m, 4H), 2.46(m, 3H), 2.25 (s, 3H), 1.91 (t, 2H), 1.70 (m, 3H), 1.60 (s, 2H). 187

¹H-NMR (300 MHz, CDCl₃) δ 7.82 (m, 2H), 7.62 (s, 1H), 7.48 (d, 1H), 7.38(m, 2H), 7.13 (m, 3H), 7.04 (d, 1H), 6.42 (dd, 1H), 6.24 (m, 1H), 5.76(dd, 1H), 3.68 (m, 4H), 3.47 (s, 2H), 2.40 (m, 4H); MS (ESI⁺): m/z =488.17 [M + H]⁺. 188

¹H-NMR (300 MHz, DMSO-d₆) δ 10.40 (s, 1H), 9.42 (s, 1H), 8.29 (d, 1H),7.74 (s, 1H), 7.58 (d, 1H), 7.47 (m, 4H), 7.04 (m, 2H), 6.44 (dd, 1H),6.25 (d, 1H), 5.71 (d, 1H), 3.70 (s, 3H); MS (ESI⁺): m/z = 447.64 [M +H]⁺.

TABLE 5d Example Structure Analysis data 189

¹H-NMR (300 MHz, DMSO-d₆) δ 10.37 (brs, 1H), 9.49 (brs, 1H), 8.30 (d,1H) 7.73 (s, 1H), 7.59-7.47 (m, 4H), 7.37 (d, 1H), 7.03-7.00 (m, 3H),6.48-6.41 (m, 1H), 6.31-6.29 (m, 1H), 5.79-5.92 (m, 1H), 3.59 (s, 3H),3.55 (s, 3H), 3.16 (s, 2H); MS (ESI⁺): m/z = 511.11 [M + H]⁺. 190

¹H-NMR (300 MHz, DMSO-d₆) δ 10.4 (s, 1H), 9.39 (s, 1H), 8.29 (d, 1H),7.49 (d, 2H), 7.44 (m, 3H), 7.35 (d, 1H), 7.08 (dd, 1H), 6.95 (d, 2H),6.42 (q, 1H), 6.24 (dd, 1H), 5.77 (dd, 1H), 3.51 (m, 2H), 2.60 (m, 2H);MS (ESI⁺): m/z = 433 [M + H]⁺. 191

¹H-NMR (300 MHz, CDCl₃) δ 7.83 (d, 1H), 7.54 (s, 1H), 7.45 (s, 1H), 7.41(d, 1H), 7.38 (m, 1H), 7.35 (m, 2H), 7.03 (m, 2H), 7.00 (s, 1H), 6.43(d, 1H), 6.31 (t, 3H), 5.74 (dd, 1H), 2.53 (m, 2H), 2.48 (m, 2H), 2.30(s, 6H); MS (ESI⁺): m/z = 460 [M + H]⁺. 192

¹H-NMR (300 MHz, CDCl₃) δ 7.81 (d, 1H), 7.69 (s, 1H), 7.38-7.29 (m, 4H),7.25-7.19 (m, 3H), 7.00 (d, 1H), 6.40 (d, 1H), 6.34 (dd, 1H), 5.72 (d,1H), 3.66 (s, 2H), 3.42-3.40 (m, 2H), 2.40-2.38 (m, 4H), 1.58-1.55 (m,4H), 1.01 (t, 3H); 193

¹H-NMR (300 MHz, CDCl₃) δ 9.01 (s, 1H), 7.97 (s, 1H), 7.86 (d, 2H), 7.71(s, 1H), 7.46 (m, 2H), 7.28 (m, 1H), 7.00 (m, 1H), 6.95 (d, 1H), 6.78(s, 1H), 6.43 (m, 2H), 5.69 (m, 1H), 3.90 (s, 2H), 3.84 (s, 3H), 2.94(m, 4H), 1.15 (m, 6H); MS (ESI⁺): m/z = 504.2 [M + H]⁺. 194

¹H-NMR (300 MHz, CD₃OD) δ 8.10 (d, 1H), 7.78 (s, 1H), 7.61-7.56 (m, 2H),7.47-7.42 (m, 1H), 7.32 (d, 1H), 7.20-7.05 (m, 3H), 6.50-6.33 (m, 2H),5.78 (d, 1H), 3.58 (s, 2H), 2.32 (s, 6H); MS (ESI⁺): m/z = 464.15 [M +H]⁺. 195

¹H-NMR (300 MHz, CD₃OD) δ 8.10 (d, 1H), 7.78-7.77 (m, 1H), 7.59-7.42 (m,3H), 7.32 (d, 1H), 7.15-7.04 (m, 3H), 6.43- 6.38 (m, 2H), 5.78 (dd, 1H),3.59-3.57 (m, 2H), 2.91-2.88 (m, 1H), 2.88-2.75 (m, 2H), 2.52-2.48 (m,1H), 2.32-2.20 (m, 6H), 2.09-1.92 (m, 1H), 1.78-1.63 (m, 1H); MS (ESI⁺):m/z = 533.21 [M + H]⁺.

TABLE 5e Example Structure Analysis data 196

¹H-NMR (300 MHz, CD₃OD) δ 8.16 (d, 1H), 7.82 (s, 1H), 7.50-7.44 (m, 3H),7.33 (d, 1H), 7.19-7.05 (m, 3H), 6.51-6.34 (m, 2H), 5.80 (dd, 1H),3.49-3.45 (m, 2H), 2.98-2.94 (m, 2H), 2.41-2.01 (m, 9H), 1.90-1.81 (m,2H), 1.69-1.42 (m, 2H); MS (ESI⁺): m/z = 547.22 [M + H]⁺. 197

¹H-NMR (300 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.71 (s, 1H), 8.33 (d, 1H),7.76 (s, 1H), 7.50 (m, 4H), 7.29 (m, 1H), 7.07 (m, 2H), 6.43 (dd, 1H),6.24 (dd, 1H), 5.76 (dd, 1H), 3.36 (s, 2H), 2.33 (m, 8H), 2.08 (s, 3H);MS (ESI⁺): m/z = 519.2 [M + H]⁺. 198

¹H-NMR (300 MHz, CD₃OD) δ 8.11 (d, 1H), 7.74-7.73 (m, 1H), 7.60-7.58 (m,2H), 7.45 (t, 1H), 7.32 (d, 1H), 7.17-7.12 (m, 2H), 7.07-7.04 (m, 1H),6.48-6.33 (m, 2H), 5.79-5.76 (m, 1H), 3.78-3.77 (m, 2H), 2.94-2.90 (m,2H), 2.55-2.52 (m, 1H), 2.30 (s, 3H), 2.15-1.89 (m, 4H), 1.53-1.49 (m,2H); MS (ESI⁺): m/z = 533.21 [M + H]⁺. 199

¹H-NMR (300 MHz, DMSO-d₆) δ 10.35 (s, 1H), 9.27 (s, 1H), 8.27 (m, 1H),7.72 (m, 1H), 7.57 (m, 1H), 7.46 (m, 1H), 7.35 (m, 2H), 7.15 (m, H),7.06 (m, 1H), 6.52 (m, 2H), 6.43 (m, 3H), 6.23 (dd, 1H), 5.76 (dd, 1H),3.05 (m, 2H), 2.44 (m, 2H), 2.17 (s, 3H); MS (ESI⁺): m/z = 493.2 [M +H]⁺. 200

¹H-NMR (300 MHz, DMSO-d₆) δ 10.33 (s, 1H), 9.51 (s, 1H), 8.29 (d, 1H),7.74 (m, 1H), 7.46 (m, 1H), 7.41 (m, 1H), 7.37 (m, 1H), 7.23 (m, 2H),7.05 (m, H), 6.43 (m, 1H), 6.21 (dd, 1H), 5.75 (dd, 1H), 4.30 (m, 1H),3.11 (m, 2H), 2.33 (t, 2H), 2.12 (s, 6H); MS (ESI⁺): m/z = 511.2 [M +H]⁺. 201

¹H-NMR (300 MHz, DMSO-d₆) δ 10.39 (s, 1H), 9.70 (s, 1H), 8..37 (d, 1H),8.08 (s, 1H), 7.80 (d, 1H), 7.60 (m, 2H), 7.50 (m, 2H), 7.27 (m, 1H),7.12 (m, 2H), 6.43 (m, 1H), 6.31 (m, 1H), 5.82 (m, 1H), 3.41 (m, 4H),2.33 (m, 4H), 2.24 (s, 3H); MS (ESI⁺): m/z = 548.2 [M + H]⁺. 202

¹H-NMR (300 MHz, CDCl₃) δ 7.86 (d, 1H), 7.66 (m, 3H), 7.38 (m, 2H), 7.28(d, 1H), 7.21 (m, 2H), 7.13 (s, 1H), 7.03 (m, 1H), 6.45 (m, 1H), 6.27(m, 1H), 5.77 (m, 1H), 3.54 (s, 2H), 2.65 (m, 8H), 2.26 (s, 3H), 1.90(m, 4H), 1.45 (m, 4H); MS (ESI⁺): m/z = 618.2 [M + H]⁺.

TABLE 5f Example Structure Analysis data 203

¹H-NMR (300 MHz, CD₃OD) δ 8.07 (d, 1H), 7.83 (s, 1H), 7.77 (s, 1H), 7.53(d, 1H), 7.42 (d, 2H), 7.29 (d, 1H), 7.03 (d, 1H), 6.41 (s, 1H), 6.38(d, 1H), 5.77 (dd, 1H), 3.76-3.74 (m, 2H), 3.26-3.24 (m, 2H), 2.48 (dd,2H), 2.44 (d, 2H), 2.37 (m, 1H), 1.09 (t, 3H); MS (ESI⁺): m/z = 563.4[M + H]⁺. 204

¹H-NMR (300 MHz, DMSO-d₆) δ 10.33 (s, 1H), 9.22 (s, 1H), 8.24 (m, 1H),7.75 (m, 1H), 7.57 (m, 1H), 7.42 (m, 1H), 7.30 (m, 2H), 7.14 (m, H),7.06 (m, 1H), 6.52 (m, 2H), 6.43 (m, 3H), 6.23 (dd, 1H), 5.76 (dd, 1H),3.05 (m, 2H), 2.44 (m, 2H), 2.17 (s, 3H); MS (ESI⁺): m/z = 509.1 [M +H]⁺. 205

¹H-NMR (300 MHz, CDCl₃) δ 7.97 (s, 1H), 7.86 (d, 1H), 7.83 (d, 1H), 7.73(s, 1H), 7.48 (d, 1H), 7.41 (t, 1H), 7.28 (d, 1H), 7.06 (m, 2H), 6.99(d, 1H), 6.81 (s, 1H), 6.46 (dd, 1H), 6.30 (dd, 1H), 5.79 (dd, 1H), 3.38(s, 2H), 2.28 (s, 3H), 2.26 (s, 6H); MS (ESI⁺): m/z = 459.94 [M + H]⁺.

Example 206 Preparation ofN-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylamino)phenyl)acrylamide

The procedure of Example 1 was repeated except for using3-nitrobenzeneamine (0.05 mmol), instead of 3-nitrophenol in step 3) ofExample 1, to obtain 5 mg of the title compound (final yield: 55%).

¹H-NMR (300 MHz, CDCl₃) δ 8.10 (m, 1H), 7.90 (d, 1H), 7.51 (m, 3H), 7.42(m, 1H), 7.28 (t, 1H), 7.10 (d, 1H), 6.89 (d, 2H), 6.39 (m, 2H), 5.79(d, 1H), 3.29 (m, 4H), 2.68 (m, 4H), 2.38 (s, 3H);

MS (ESI⁺): m/z=486.2 [M+H]⁺.

The procedure of Example 206 or a similar procedure was repeated exceptfor using various amine derivatives of Z—NH₂ (Z has the same meaning asdefined in the present invention), instead of5-(4-methylpiperazin-1-yl)piridin-2-amine in Example 1, to obtain thetitle compounds of Examples 207 to 217 as shown in Tables 6a and 6b.

TABLE 6a Example Structure Analysis data 207

¹H-NMR (300 MHz, DMSO-d₆) δ 8.14 (s, NH), 7.80 (d, 1H), 7.68 (d, 1H),7.59 (s, NH), 7.42 (m, 2H), 7.32 (m, 2H), 7.00 (m, 2H), 6.49 (d, 1H),6.31 (m, 1H), 5.77 (d, 1H), 3.00 (d, 2H), 2.75 (m, 1H), 2.34 (s, 3H),2.08 (m, 2H), 1.75 (m, 4H); MS (ESI⁺): m/z = 500.2 [M + H]⁺. 208

¹H-NMR (300 MHz, DMSO-d₆) δ 10.12 (s, NH), 9.59 (s, NH), 8.80 (s, NH),8.01 (m, 2H), 7.59 (m 3H), 7.41 (d, 1H), 7.31 (t, 1H), 7.19 (d, 1H) 6.80(d, 2H), 6.48 (m, 1H), 6.25 (d, 1H), 5.78 (d, 1H), 3.01 (br, 4H), 2.71(m, 1H), 2.61 (br, 4H), 1.01 (d, 6H); MS (ESI⁺): m/z = 514.2 [M + H]⁺.209

¹H-NMR (300 MHz, DMSO-d₆) δ 10.20 (s, 1H), 9.53 (s, 1H), 9.00 (s, 1H),8.07 (m, 2H), 7.67 (d, 2H), 7.50 (m, 2H), 7.29 (dd, 1H), 7.18 (d, 1H),7.02 (d, 2H), 6.46 (dd, 1H), 6.25 (dd, 1H), 5.74 (dd, 1H), 2.88 (m, 2H),2.35 (m, 1H), 2.22 (s, 3H), 2.01 (m, 2H), 1.62 (m, 4H); MS (ESI⁺) m/z =485.2 [M + H]⁺. 210

¹H-NMR (300 MHz, CDCl₃) δ 8.09 (s, 1H), 7.66-7.65 (d, 1H), 7.59- 7.56(m, 2H), 7.51 (brs, 1H), 7.40-7.31 (m, 3H), 7.23-7.21 (d, 1H), 7.17-7.14(m, 2H), 7.09 (s, 1H), 6.75 (s, 1H), 6.50-6.44 (m, 1H), 5.81-5.77 (m,1H), 6.30 (m, 1H), 2.97-2.80 (m, 1H), 2.32 (s, 3H), 1.97-1.75 (m, 6H);MS (ESI⁺): m/z = 485.2 [M + H]⁺. 211

¹H-NMR (300 MHz, DMSO-d₆) δ 10.13 (s, 1H), 9.49 (s, 1H), 8.84 (s, 1H),8.04 (m, 2H), 7.62 (m, 2H), 7.53 (m, 1H), 7.40 (m, 1H), 7.28 (m, 1H),7.16 (m, 1H), 6.75 (m 2H), 6.44 (m, 1H), 6.24 (m, 1H), 5.74 (m, 1H),3.95 (t, 2H), 2.57 (t, 2H), 2.19 (s, 6H); MS (ESI⁺): m/z = 475.2 [M +H]⁺. 212

¹H-NMR (300 MHz, DMSO-d₆) δ 10.20 (s, 1H), 9.50 (s, 1H), 8.87 (s, 1H),8.05 (m, 2H), 7.63 (m, 2H), 7.55 (m, 1H), 7.42 (m, 1H), 7.31 (m, 1H),7.17 (m, 1H), 6.76 (m 2H), 6.47 (m, 1H), 6.25 (m, 1H), 5.75 (m, 1H),3.91 (t, 2H), 2.34 (t, 2H), 2.14 (s, 6H), 1.80 (m, 2H); MS (ESI⁺): m/z =489.2 [M + H]⁺. 213

¹H-NMR (300 MHz, DMSO-d₆) δ 10.14 (s, 1H), 9.54 (s, 1H), 8.99 (s, 1H),8.06-8.03 (m, 2H), 7.69-7.67 (m, 2H), 7.56-7.54 (m, 1H), 7.45-7.42 (m,1H), 7.32-7.27 (m, 1H), 7.19-7.18 (d, 1H), 7.05-7.02 (m, 2H), 6.47-6.41(m, 1H), 6.29-6.22 (m, 1H), 5.77-5.73 (m, 1H), 2.67 (m, 4H), 2.38 (s,6H); MS (ESI⁺): m/z = 459.1 [M + H]⁺.

TABLE 6b Example Structure Analysis data 214

¹H-NMR (300 MHz, CDCl₃) δ 8.13 (s, 1H), 7.68-7.66 (d, 1H), 7.59- 7.56(m, 2H), 7.42-7.32 (4H), 7.24-7.22 (d, 1H), 7.16-7.13 (m, 2H), 7.05 (s,1H), 6.96 (s, 1H), 6.50-6.44 (m, 1H), 6.22 (m, 1H), 5.82- 5.78 (m, 1H),2.81-2.52 (m, 12H), 2.32 (s, 3H); MS (ESI⁺): m/z = 514.2 [M + H]⁺. 215

¹H-NMR (300 MHz, DMSO-d₆) δ 10.06 (s, NH), 9.50 (s, NH), 9.02 (s, NH),8.00 (d, 1H), 7.96 (s, 1H), 7.63 (d, 1H), 7.46 (d, 1H), 7.37 (m, 2H),7.25 (t, 1H), 7.12 (d, 1H), 6.81 (t, 1H), 6.41 (m, 1H), 6.19 (d, 1H),5.64 (d, 1H), 2.91 (m, 4H), 2.41 (m, 4H), 2.13 (s, 3H); MS (ESI⁺): m/z =504.2 [M + H]⁺. 216

¹H-NMR (300 MHz, DMSO-d₆) δ 10.12 (s. NH), 9.60 (s, NH), 9.21 (s, NH),8.08 (d, 1H), 8.01 (s, 1H), 7.77 (d, 1H), 7.53 (d, 1H), 7.41 (m, 2H),7.34 (t, 1H), 7.21 (d, 1H), 7.07 (t, 1H), 6.45 (m, 1H), 6.26 (d, 1H),5.72 (d, 1H), 2.85 (m, 2H), 2.60 (m, 1H), 1.90 (m, 2H), 1.64 (m, 4H); MS(ESI⁺): m/z = 503.2 [M + H]⁺. 217

¹H-NMR (300 MHz, DMSO-d₆) δ 10.23 (s, NH), 9.49 (s, NH), 8.84 (s, NH),8.02 (d, 1H), 7.57 (m, 2H), 7.41 (d, 1H), 7.29 (m, 2H), 7.18 (d, 1H),6.65 (t, 1H), 6.48 (m, 1H), 6.43 (m, 1H), 5.75 (d, 1H), 4.50 (d, 1H),3.11 (m, 1H), 2.70 (m, 2H), 2.16 (s, 3H), 2.01 (m, 2H), 1.80 (m, 2H),1.40 (m, 2H); MS (ESI⁺): m/z = 518.2 [M + H]⁺.

Example 218 Preparation ofN-(4-fluoro-3-(2-(4-(4-methyl-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide

Step 1) Preparation of N-(4-fluoro-3-nitro-phenyl)-acrylamide

2 g (12.81 mmol) of 4-fluoro-3-nitroaniline and 3.2 g (38.43 mmol) ofsodium bicarbonate were diluted in 20 mL of tetrahydrofuran and 5 mL ofdistilled water, and 1.14 mL (14.09 mmol) of acryloyl chloride wasslowly added thereto at 0° C., and stirred for 1 hour. Upon thecompletion of the reaction, the resulting mixture was diluted withethylacetate and washed with a saturated aqueous solution of sodiumbicarbonate. The organic layer was separated, dried over anhydrousNa₂SO₄, and filtered and distilled under a reduced pressure to obtain 2g of the title compound (yield: 74%).

¹H-NMR (300 MHz, DMSO-d₆) δ 10.58 (s, 1H), 8.58 (m, 1H), 7.91 (m, 1H),7.54 (t, 1H), 6.35 (m, 2H), 5.81 (m, 1H);

Step 2) Preparation of N-(3-amino-4-fluoro-phenyl)-acrylamide

2.65 g (47.59 mmol) of Iron and 0.31 mL (3.80 mmol) of 12 N aqueoushydrochloric acid were diluted in 40 mL of 50% aqueous ethanol andstirred for 1 hour at 100° C. 2.00 g (9.51 mmol) of the compoundobtained in the Step 1 was added thereto, and stirred for 1 hour at 100°C. Upon the completion of the reaction, the resulting mixture wasfiltered over a short bed of Celite filter to remove Iron, and distilledunder a reduced pressure. The resulting residue was diluted withdichloromethane and washed with a saturated aqueous solution of sodiumbicarbonate. The organic layer was separated, dried over anhydrousNa₂SO₄, and filtered and distilled under a reduced pressure. Theresulting residue was separated by column chromatography(n-hexane:ethylacetate (1:1, v/v)) to obtain 1.5 g of the title compound(yield: 75%).

¹H-NMR (300 MHz, DMSO-d₆) δ 9.87 (s, 1H), 7.17 (m, 1H), 6.89 (t, 1H),6.75 (m, 1H), 6.39 (m, 1H), 6.20 (m, 1H), 5.70 (m, 1H), 5.16 (s, 2H);

Step 3) Preparation ofN-(3-(2-chloro-thieno[3,2-d]pyrimidin-4-ylamino)-4-fluoro-phenyl)-acrylamide

The compound obtained in Step 2) of Example 1 and 461 mg (2.22 mmol) ofthe compound obtained in the Step 2) were dissolved in 5 ml of1-propanol, and 0.6 mL (3.33 mmol) of diisopropylethylamine was addedthereto, and stirred for 24 hours at 110° C. Upon the completion of thereaction, the resulting mixture was cooled to 0° C. to form solid, andfiltered under a reduced pressure while washing with propanol. Theresulting solid was dried over under a reduce pressure to obtain 270 mgof the title compound (yield: 36%).

¹H-NMR (300 MHz, DMSO-d₆) δ 10.31 (s, 1H), 10.22 (s, 1H), 8.25 (d, 1H),7.86 (m, 1H), 7.59 (m, 1H), 7.40 (d, 1H), 7.32 (t, 1H), 6.42 (m, 1H),6.29 (m, 1H), 5.76 (m, 1H);

Step 4) Preparation ofN-(4-fluoro-3-(2-(4-(4-methyl-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide

100 mg (0.30 mmol) of the compound obtained in the Step 3) was dissolvedin 3 ml of 2-butanol, and 55 mg (0.28 mmol) of4-(4-methylpiperazin-1-yl)benzeneamine and 42 μl (0.57 mmol) oftrifluoroacetic acid were added thereto, and stirred for 5 hours at 100°C. Upon the completion of the reaction, the resulting mixture wasdiluted with ethylacetate and washed with a saturated aqueous solutionof sodium bicarbonate. The organic layer was separated, dried overanhydrous Na₂SO₄, and filtered and distilled under a reduced pressure.The resulting residue was separated by column chromatography(dichloromethane:methanol (10:1, v/v)) to obtain 77 mg of the titlecompound (yield: 50%).

¹H-NMR (300 MHz, DMSO-d₆) δ 10.26 (s, 1H), 9.38 (s, 1H), 8.77 (s, 1H),8.02 (d, 1H), 7.82 (d, 1H), 7.62 (m, 1H), 7.44 (d, 2H), 7.30 (t, 1H),7.15 (d, 1H), 6.68 (m, 2H), 6.40 (m, 1H), 6.22 (m, 1H), 5.73 (m, 1H),2.96 (m, 4H), 2.42 (m, 4H), 2.20 (s, 3H);

MS (ESI⁺): m/z=504.1 [M+H]⁺.

Example 219 Preparation ofN-(4-fluoro-3-(2-(3-fluoro-4-(4-methyl-piperazin-1-yl)-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide

A similar procedure as the procedure of Step 4) of Example 218 wascarried out except for using 3-fluoro-4-(4-methylpiperazin-1-yl)anilline(0.03 mmol), instead of 4-(4-methylpiperazin-1-yl)benzeneamine in theStep 4) of Example 218, to obtain 8 mg of the title compound (finalyield: 50%).

¹H-NMR (300 MHz, DMSO-d₆) δ 10.25 (s, 1H), 9.50 (s, 1H), 9.08 (s, 1H),8.07 (d, 1H), 7.85 (d, 1H), 7.59 (m, 2H), 7.26 (m, 2H), 7.19 (d, 1H),6.78 (t, 1H), 6.38 (m, 1H), 6.27 (m, 1H), 5.75 (m, 1H), 2.87 (m, 4H),2.25 (m, 4H), 2.21 (s, 3H);

MS (ESI⁺): m/z=522.2 [M+H]⁺.

Example 220 Preparation ofN-(3-(2-(4-dimethylaminomethyl-phenylamino)-thieno[3,2-d]pyrimidin-4-ylamino)-phenyl)-acrylamide

A procedure similar to the procedure of the Step 4) of Example 218 wascarried out except for using 0.67 g (1.94 mmol) ofN-(3-(2-chloro-thieno[3,2-d]pyrimidin-4-ylamino)phenyl)acrylamideobtained in Step 1) to 3) of Example 218 and 0.29 g (1.94 mmol) of4-((dimethylamino)methyl)anilline to obtain 0.69 g of the titlecompounds (yield: 80%).

¹H-NMR (300 MHz, CDCl₃) δ 8.11 (d, 2H), 7.63 (dd, 3H), 7.55 (m, 4H),7.18 (m, 2H), 7.05 (s, 1H), 6.45 (d, 1H), 6.30 (q, 1H), 5.74 (d, 1H),3.38 (s, 2H), 2.01 (s, 6H);

MS (ESI⁺): m/z=467.1 [M+H]⁺.

A procedure similar to the procedure of Example 220 was carried outexcept for using 4-(piperidin-1-yl)methylphenylamine and2-methoxy-4-(piperidin-1-yl)methylphenylamine to obtain the titlecompounds of Examples 221 and 222 as shown in Table 7.

TABLE 7 Example Structure Analysis data 221

1H-NMR (300 MHz, DMSO-d₆) δ 10.36 (s, NH), 8.32 (d, 1H), 8.30 (m, 2H),7.61 (d, 1H), 7.36 (d, 1H), 7.09 (d, 1H), 6.88 (s, NH), 6.61 (d, 1H),6.42 (dd, 1H), 6.23 (d, 1H), 5.75 (d, 1H), 3.79 (s, 3H), 3.33 (s, 2H),2.28 (br, 4H), 1.48 (br, 4H), 1.24 (br, 2H); MS (ESI⁺): m/z = 485.2 [M +H]⁺. 222

¹H-NMR (300 MHz, DMSO-d₆) δ 10.36 (s, NH), 8.32 (d, 1H), 8.30 (m, 2H),7.61 (d, 1H), 7.48 (t, 1H), 7.36 (d, 1H), 7.09 (d, 1H), 6.88 (s, NH),6.61 (d, 1H), 6.42 (dd, 1H), 6.23 (d, 1H), 5.75 (d, 1H), 3.79 (s, 3H),3.33 (s, 2H), 2.28 (br, 4H), 1.48 (br, 4H), 1.24 (br, 2H); MS (ESI⁺):m/z = 516.1 [M + H]⁺.

Example 223 Preparation ofN-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylthio)phenyl)acrylamide

Step 1) Preparation of tert-butyl3-(2-chlorothieno[3,2-d]pyrimidin-4-ylthio)phenylcarbamate

1.1 g (5.32 mmol) of the compound obtained in Step 2) of Example 1 wasdissolved in 30 ml of N,N-dimethylsulfonamide, and 1.2 g (5.32 mmol) oftert-butyl-3-mercaptophenylcarbamate and 3.4 g (10.6 mmol) of cesiumcarbonate were added thereto, and stirred for 1 hour at roomtemperature. Upon the completion of the reaction, the distilled waterwas added to the resulting mixture to form a solid, and the resultingmixture was filtered under a reduced pressure while washing withdistilled water. The resulting solid was dried over under a reducepressure to obtain 1.5 g of the title compound (yield: 70%).

¹H-NMR (300 MHz, CDCl₃) δ 7.92 (d, 1H), 7.77 (s, 1H), 7.56 (d, 1H),7.45-7.36 (m, 3H), 1.54 (s, 9H).

Step 2) Preparation of tert-butyl3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylthio)phenylcarbamate

1.5 g (3.72 mmol) of the compound obtained in the Step 1) was dissolvedin 30 ml of 2-butanol, and 0.8 g (3.72 mmol) of4-(4-methylpiperazin-1-yl)benzeneamine and 0.4 mL (3.72 mmol) oftrifluoroacetic acid were added thereto. The mixture was stirred for 10hours at 100° C., upon the completion of the reaction, diluted withdichloromethane and washed with a saturated aqueous solution of sodiumbicarbonate. The organic layer was dried over anhydrous Na₂SO₄, andfiltered and distilled under a reduced pressure. The residue wasseparated by column chromatography (dichloromethane:methanol (20:1,v/v)) to obtain 1.0 g of the title compound (yield: 46%).

¹H-NMR (300 MHz, CDCl₃) δ 7.73 (d, 1H), 7.63 (m, 1H), 7.60 (m, 1H),7.39-7.30 (m, 2H), 7.28-7.21 (m, 2H), 7.15 (d, 1H), 6.76 (d, 2H), 3.25(m, 4H), 2.58 (m, 4H), 2.33 (s, 3H), 1.54 (s, 9H).

Step 3) Preparation of4-(3-aminophenylthio)-N-(4-(4-methylpiperazin-1-yl)phenyl)thieno[3,2-d]pyrimidin-2-amine

1.0 g (1.82 mmol) of the compound obtained in the Step 2) was dissolvedin 20 ml of dichloromethane, and 10 mL of trifluoroacetic acid was addedthereto, and stirred for 2 hours at room temperature. Upon thecompletion of the reaction, the resulting mixture was distilled under areduced pressure to remove solvent, and the resulting residue wasbasified (pH=8) with a saturated aqueous solution of sodium bicarbonate,and extracted with chloroform. The organic layer was separated, driedover anhydrous Na₂SO₄, and filtered and distilled under a reducedpressure and dried over to obtain 603 mg of the title compound (yield:75%).

¹H-NMR (300 MHz, CD₃OD) δ 7.96 (d, 1H), 7.33 (d, 2H), 7.21 (t, 1H), 7.17(d, 1H), 7.02 (m, 1H), 6.94 (m, 2H) 6.80 (d, 2H), 3.14 (m, 4H), 2.65 (m,4H).

Step 4) Preparation ofN-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3.2-d]pyrimidin-4-ylthio)phenyl)acrylamide

A similar procedure as the procedure of Step 6) of Example 1 was carriedout except for using the compound obtained in the Step 3), instead ofthe compound obtained step 5), to obtain 452 mg of the title compound(yield: 67%).

¹H-NMR (300 MHz, CDCl₃) δ 7.78 (m, 1H), 7.75 (d, 1H), 7.46-7.41 (m, 3H),7.20 (d, 2H), 7.18 (d, 1H), 6.77 (d, 2H), 6.41 (d, 1H), 6.21 (dd, 1H),5.78 (d, 1H), 3.12 (m, 4H), 2.60 (m, 4H), 2.36 (s, 3H);

MS (ESI⁺): m/z=503.7 [M+H]⁺.

The procedure of Example 223 or a similar procedure was repeated exceptfor using 3-fluoro-4-morpholin-4-ylphenylamine and3-fluoro-4-(1-methyl-piperidin-4-yl)phenylamine, instead of54-(4-methylpiperazin-1-yl)phenylamine in step 2) of Example 223, toobtain the title compounds of Examples 224 and 225 as shown in Table 8.

TABLE 8 Example Structure Analysis data 224

¹H-NMR (300 MHz, DMSO-d₆) δ 10.37 (s, 1H), 9.57 (s, 1H), 8.24 (d, 1H),8.01 (s, 1H), 7.98 (m, 1H), 7.50 (t, 1H), 7.41 (m, 1H), 7.31 (m, 2H),7.15 (m, 1H), 6.73 (m, 1H), 6.42 (m, 1H), 6.27 (m, 1H), 5.74 (m, 1H),3.70 (m, 4H), 2.85 (m, 4); MS (ESI⁺): m/z = 508.1 [M + H]⁺. 225

¹H-NMR (300 MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.53 (d, 1H), 8.36 (d, 1H),8.00 (d, 1H), 7.62 (t, 1H), 7.46 (d, 2H), 7.32 (d, 1H), 6.93 (d, 2H),3.83 (d, 2H), 3.48 (d, 2H), 3.12 (m, 4H), 2.83 (s, 3H); MS (ESI⁺): m/z =520.2 [M + H]⁺.

Example 226 Preparation of(E)-4-(dimethylamino)-N-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylthio)phenyl)but-2-enamide

40 mg (0.09 mmol) of the compound obtained in Step 2 of Example 223 wasdissolved in 1.5 mL of pyridine, and 22 mg (0.14 mmol) of(E)-4-(dimethylamino)-2-butenoic acid hydrochloride and 35 mg (0.18mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloridewere added thereto, and stirred for 30 minutes at 80° C. Upon thecompletion of the reaction, the resulting mixture was diluted with mixedsolvent of chloroform:2-propanol (3:1(v/v)) and washed with saturatedsaline. The organic layer was separated, dried over anhydrous Na₂SO₄,and filtered and distilled under a reduced pressure. The resultingresidue was separated by column chromatography(dichloromethane:methanol=6:1 (v/v)) to obtain 2 mg of the titlecompound (yield: 4%).

¹H-NMR (300 MHz, CDCl₃) δ 8.10 (m, 1H), 8.02 (d, 1H), 7.93 (s, 1H), 7.50(t, 1H), 7.42 (m, 1H), 7.21 (m, 3H), 6.90 (m, 1H), 6.74 (d, 2H), 6.28(d, 1H), 3.20 (d, 2H), 3.10 (t, 4H), 2.66 (t, 4H), 2.39 (s, 3H), 2.17(s, 6H);

MS (ESI⁺): m/z=560.2 [M+H]⁺.

Example 227 Preparation ofN-(3-(2-(4-(4-methylpiperazin-1-yl)phenylamino)thieno[3,2-d]pyrimidin-4-ylsulfinyl)phenyl)acrylamide

11 mg (0.02 mmol) of the compound obtained in Example 223 was dissolvedin 1.0 mL of dichloromethane, and 20 mg (0.04 mmol) ofm-chloroperoxybenzoic acid was added thereto, and stirred for 60 minutesat room temperature. Upon the completion of the reaction, the resultingmixture was diluted with chloroform and washed with a saturated aqueoussolution of sodium bicarbonate. The organic layer was separated, driedover anhydrous Na₂SO₄, and filtered and distilled under a reducedpressure. The resulting residue was separated by column chromatography(dichloromethane:methanol=6:1 (v/v)) to obtain 3.0 mg of the titlecompound (yield: 25%).

¹H-NMR (300 MHz, CD₃OD) δ 8.08 (m, 1H), 8.01 (d, 1H), 7.92 (m, 1H), 7.51(t, 1H), 7.46 (m, 1H), 7.22 (m, 3H), 6.73 (d, 1H), 6.38 (m, 2H), 5.76(dd, 1H), 3.63-3.56 (m, 4H), 3.42-3.34 (m, 4H), 3.23 (s, 3H);

MS (ESI⁺): m/z=519.3 [M+H]⁺.

Example 228 Preparation ofN-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)furo[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide

Step 1) Preparation of 2-chloro-4-(3-nitrophenoxy)-furo[3,2-d]pyrimidine

6.4 g (33.9 mmol) of 2,4-dichlorofuro[3,2-d]pyrimidine (see:International Publication Number WO 2008073785 and WO 2008152394) wasdissolved in 32 mL of methanol, and 5.7 g (40.6 mmol) of 3-nitrophenoland 12 mL (67.7 mmol) of diisopropylethylamine were added thereto, andstirred for 24 hours at room temperature. Upon the completion of thereaction, the resulting solid was filtered and dried over under areduced pressure to obtain 6.3 g of the title compound (yield: 64%).

¹H-NMR (300 MHz, DMSO-d₆) δ 8.61 (s, 1H), 8.33 (s, 1H), 8.21 (d, 1H),7.90 (d, 1H), 7.79 (m, 1H), 7.27 (s, 1H);

Step 2) Preparation ofN-[4-(4-methyl-piperazin-1-yl)-phenyl]-4-(3-nitrophenoxy)-furo[3,2-d]pyrimidin-2-amine

2.5 g (8.6 mmol) of the compound obtained in the Step 1) was dissolvedin 50 ml of 2-butanol, and 2.0 g (10.3 mmol) of4-(4-methyl-piperazin-1-yl)anilline and 1.5 mL (8.6 mmol) oftrifluoroacetic acid were added thereto. The reaction mixture wasstirred for 12 hours at 100° C., upon the completion of the reaction,diluted with dichloromethane and washed with a saturated aqueoussolution of sodium bicarbonate. The organic layer was separated, driedover anhydrous Na₂SO₄, and filtered and distilled under a reducedpressure and dried over. The resulting residue was separated by columnchromatography (dichloromethane:methanol=20:1 (v/v)) to obtain 2.0 g ofthe title compound (yield: 53%).

¹H-NMR (300 MHz, CDCl₃) δ 8.20 (s, 2H), 7.85 (s, 1H), 7.64 (s, 2H), 7.30(s, 1H), 6.79 (m, 4H), 3.14 (m, 4H), 2.60 (m, 4H), 2.37 (s, 3H);

Step 3) Preparation of4-(3-aminophenoxy)-N-[4-(4-methyl-piperazin-1-yl)-phenyl]-furo[3,2-d]pyrimidin-2-amine

1.3 g (22.4 mmol) of Iron and 2 mL of 12 N aqueous hydrochloric acidwere diluted in 10 mL of 50% aqueous ethanol and stirred for 10 minutesat 100° C. 2.0 g (4.5 mmol) of the compound obtained in the Step 2) wasdissolved in 10 ml of 50% aqueous ethanol, added to flask where the ironwas activated, and stirred for 1 hour at 100° C. Upon the completion ofthe reaction, the resulting mixture was filtered over a short bed ofCelite filter to remove Iron, and distilled under a reduced pressure.The resulting residue was diluted with dichloromethane and washed with asaturated aqueous solution of sodium bicarbonate. The organic layer wasseparated, dried over anhydrous Na₂SO₄, and filtered and distilled undera reduced pressure to obtain 1.8 g of the title compound (yield: 97%).

¹H-NMR (300 MHz, CDCl₃) δ 7.79 (s, 1H), 7.32 (d, 2H), 7.24 (m, 1H), 6.84(m, 2H), 6.75 (s, 1H), 6.65 (m, 3H), 3.22 (m, 4H), 2.60 (m, 4H), 2.36(s, 3H);

Step 4) Preparation ofN-(3-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-furo[3,2-d]pyrimidin-4-yloxy}-phenyl)-acrylamide

1.8 g (4.3 mmol) of the compound obtained in the Step 3) and 1.1 g (23.0mmol) of sodium bicarbonate were diluted with 20 ml of tetrahydrofuranand 5 mL of distilled water, and 0.4 mL (4.3 mmol) of acryloyl chloridewas slowly added thereto at 0° C., and stirred for 30 minutes. Upon thecompletion of the reaction, the resulting mixture was diluted withdichloromethane and washed with a saturated aqueous solution of sodiumbicarbonate. The organic layer was separated, dried over anhydrousNa₂SO₄, and filtered and distilled under a reduced pressure and driedover. The resulting residue was separated by column chromatography(chloroform:methanol=20:1 (v/v)) to obtain 940 mg of the desiredcompound (yield: 46%).

¹H-NMR (300 MHz, CD₃OD) δ 8.04 (s, 1H), 7.68 (d, 2H), 7.45 (t, 1H), 7.32(d, 2H), 7.03 (d, 1H), 6.78 (m, 3H), 6.45 (m, 2H), 5.80 (d, 1H), 3.08(m, 4H), 2.61 (m, 4H), 2.35 (s, 3H);

MS (ESI⁺): m/z=470.2 [M+H]⁺.

The procedure of Example 228 or a similar procedure was repeated exceptfor using various amine derivatives of Z—NH₂ (Z has the same meaning asdefined in the present invention), instead of4-(4-methylpiperazin-1-yl)benzeneamine in step 2) of Example 228, toobtain the title compounds of Examples 229 to 237 as shown in Tables 9aand 9b.

TABLE 9a Example Structure Analysis data 229

¹H-NMR (300 MHz, CD₃OD) δ 8.04 (s, 1H), 7.67 (d, 2H), 7.45 (t, 1H), 7.31(d, 2H), 7.04 (d, 1H), 6.78 (m, 3H), 6.40 (m, 2H), 5.79 (d, 1H), 3.23(m, 4H), 2.76 (m, 5H), 1.15 (d, 6H); MS (ESI⁺): m/z = 498.2 [M + H]⁺.230

¹H-NMR (300 MHz, CD₃OD) δ 8.03 (s, 1H), 7.73 (s, 2H), 7.45 (m, 1H), 7.31(d, 2H), 7.04 (m, 1H), 6.82 (s, 3H), 6.49 (m, 2H), 5.80 (d, 1H), 3.81(m, 4H), 3.01 (m, 4H); MS (ESI⁺): m/z = 457.1 [M + H]⁺. 231

¹H-NMR (300 MHz, CD₃OD) δ 8.14 (s, 1H), 7.83 (s, 2H), 7.70 (s, 1H), 7.50(m, 2H), 7.33 (m, 1H), 7.11 (d, 2H), 6.87 (s, 1H), 6.47 (m, 2H), 5.83(d, 1H), 3.66 (s, 2H), 2.16 (s, 6H); MS (ESI⁺): m/z = 429.1 [M + H]⁺.232

¹H-NMR (300 MHz, CD₃OD) δ 8.03 (s, 1H), 7.70 (s, 1H), 7.60 (d, 1H), 7.40(m, 3H), 7.02 (d, 3H), 6.79 (s, 1H), 6.40 (m, 2H), 5.76 (d, 1H), 3.30(m, 2H), 2.90 (d, 2H), 2.25 (d, 6H), 2.15 (m, 1H), 2.00 (m, 2H), 1.80(m, 2H), 1.50 (m, 2H); MS (ESI⁺): m/z = 512.2 [M + H]⁺. 233

¹H-NMR (300 MHz, CD₃OD) δ 8.13 (s, 1H), 7.70 (s, 1H), 7.60 (m, 3H), 7.45(m, 2H), 7.05 (m, 1H), 6.89 (s, 1H), 6.69 (m, 1H), 6.38 (m, 2H), 5.77(d, 1H); MS (ESI⁺): m/z = 451.1 [M + H]⁺. 234

¹H-NMR (300 MHz, CDCl₃) δ 7.96 (s, 1H), 7.64 (brs, 1H), 7.58-7.52 (m,2H), 7.40-7.37 (m, 1H), 7.12 (m, 1H), 7.04 (m, 1H), 6.94-6.92 (m, 2H),6.80-6.74 (m, 2H), 6.40 (m, 1H), 6.29- 6.25 (m, 1H), 5.79-5.75 (m, 1H),3.79 (s, 3H), 3.48 (s, 3H), 3.02 (m, 4H), 2.61 (m, 4H), 2.35 (s, 3H); MS(ESI⁺): m/z = 501.2 [M + H]⁺. 235

¹H-NMR (300 MHz, CD₃OD) δ 8.07 (s, 1H), 7.75 (s, 1H), 7.47 (m, 1H), 7.41(m, 2H), 7.04 (m, 3H), 6.83 (s, 1H), 6.38 (m, 2H), 5.77 (d, 1H), 2.99(d, 2H), 2.71 (m, 1H), 2.32 (s, 3H), 2.15 (m, 2H), 1.76 (m, 4H); MS(ESI⁺): m/z = 487.2 [M + H]⁺.

TABLE 9b Example Structure Analysis data 236

¹H-NMR (300 MHz, CD₃OD) δ 8.01 (s, 1H), 7.73 (s, 1H), 7.58 (d, 1H), 7.43(m, 2H), 7.28 (q, 1H), 7.02 (m, 2H), 6.77 (s, 1H), 6.57 (t, 1H), 6.40(m, 2H), 5.77 (q, 1H), 3.21 (m, 2H), 2.60 (m, 2H), 2.32 (s, 6H); MS(ESI⁺): m/z = 476.2 [M + H]⁺. 237

¹H-NMR (300 MHz, CD₃OD) δ 8.04 (s, 1H), 7.70 (s, 1H), 7.60 (d, 1H), 7.43(t, 1H), 7.26 (d, 1H), 7.04 (m, 2H), 6.79 (s, 1H), 6.62 (t, 1H), 6.40(m, 2H), 5.77 (d, 1H), 3.30 (s, 1H), 2.85 (d, 2H), 2.31(s, 3H), 2.16 (m,2H), 1.90 (m, 2H), 1.48 (m, 2H); MS (ESI⁺): m/z = 502.2 [M + H]⁺.

Preparation Example 1

Tablets for oral administration comprising each of the compounds offormula (I) obtained in Examples 1 to 237 as an active ingredient wereprepared by the conventional method based on the recipe of Table 10.

TABLE 10 Ingredient Amount/tablet Active Ingredient 100 mg  Corn Starch80 mg Lactose 80 mg Magnesium Stearate  5 mg

Preparation Example 2

Hard gelatin capsules for oral administration comprising each of thecompounds of formula (I) obtained in Examples 1 to 237 as an activeingredient were prepared by the conventional method based on the recipeof Table 11.

TABLE 11 Ingredient Amount/tablet Active Ingredient 100 mg  Corn Starch40 mg Lactose 80 mg Crystalline Cellulose 80 mg Magnesium Stearate  5 mg

Preparation Example 3

Injection formulations comprising each of the compounds of formula (I)obtained in Examples 1 to 237 as an active ingredient were prepared bythe conventional method based on the recipe of Table 12, wherein when asalt of the compound of formula (I) was used, the pH value was notmanipulated.

TABLE 12 Ingredient Amount/tablet Active Ingredient 20 mg 5% Glucosesolution 10 ml HCl (1N) adjusted to pH 4

Preparation Example 4

Injection formulations comprising each of the compounds of formula (I)obtained in Examples 1 to 237 as an active ingredient were prepared bythe conventional method based on the recipe of Table 13.

TABLE 13 Ingredient Amount/tablet Active Ingredient 20 mg  PolyethyleneGlycol 400 2 ml Sterile Water 8 ml

Test Example 1 Inhibition Test for Growth of Cancer Cell Expressing EGFR

In order to identify that the inventive compounds obtained in Examples 1to 237 selectively inhibit on the growth of the cancer cell expressingEGFR mutants compared than EGFR WT, the inhibiting test of the inventivecompounds on the cancer cell growth was conducted as follow. For thetest, a skin cancer cell line, A431 overexpressing EGFR wild-type (WT),a lung cancer cell line, HCC827 whose in-frame is deleted at position 19exon in EGFR tyrosine kinase, and NCI-H1975 expressing EGFR L858R/T790Mmutant which have resistance to the approved EGFR inhibitors such asGefitinib or Erlotinib were employed.

The inhibiting test of the inventive compounds on the cancer cell growthwas conducted in A431 (ATCC CRL-1555), HCC827 (ATCC CRL-2868) andNCI-H1975 (ATCC CRL-5908) cell lines.

A431 cell line was incubated in a high-glucose DMEM (Dulbecco's ModifiedEagle's Medium) supplemented with 10% fetal bovine serum (FBS) and 1%penicillin/streptomycin (Gibco BRL), and HCC827 and NCI-H1975 cell lineswere incubated in an RPMI medium supplemented with 10% FBS, 1%penicillin/streptomycin and 1% sodium pyruvate.

The cancer cell lines stored in a liquid nitrogen tank were each quicklythawed at 37° C., and centrifuged to remove the medium. The resultingcell pellet was mixed with a culture medium, incubated in a cultureflask at 37° C. under 5% CO₂ for 2 to 3 days, and the medium wasremoved. The remaining cells were washed with DPBS (Dulbecco's PhosphateBuffered Saline) and separated from the flask by using Tripsin-EDTA. Theseparated cells were diluted with a culture medium to a concentration of1×10⁵ A431 cells/ml, except that in case of HCC827 and NCI-H1975 cells,the dilution was carried out to 5×10⁴ cells/ml. 100 μl of the dilutedcell solution was added to each well of a 96-well plate, and incubatedat 37° C. under 5% CO₂ for 1 day. NCI-H1975 cells were starved in aRPMI-1640 medium containing 0.1% FBS and 1% penicillin/streptomycin tomaximize the reacting activities of the cell on the test compounds onthe following day.

The compounds obtained in Examples 1 to 237 were each dissolved in 99.5%dimethylsulfoxide (DMSO) to a concentration of 25 mM. In case that thetest compound was not soluble in DMSO, 1% HCl was added thereto andtreated in a 40° C. water bath for 30 mins until a complete dissolutionwas attained. The DMSO solution containing test compound was dilutedwith a culture medium to a final concentration of 100 μM, and thendiluted 10 times serially to 10⁻⁶ μM (a final concentration of DMSO wasless than 1%).

The medium was removed from each well of the 96-well plate. And then,100 μl of a test compound solution was added to each well holding thecultured cells, and the plate was incubated at 37° C. under 5% CO₂ for72 hours (except that NCI-H1975 cells were incubated for 48 hours).After removing the medium from the plate, 50 μl of 10% trichloroaceticacid was added to each well, and the plate was kept at 4° C. for 1 hourto fix the cells to the bottom of the plate. The added 10%trichloroacetic acid solution was removed from each well, the plate wasdried, 100 μl of an SRB (Sulforhodamine-B) dye solution at aconcentration of 0.4% dissolved in 1% acetic acid was added thereto, andthe resulting mixture was reacted for 10 mins at room temperature. Afterremoving the dye solution, the plate was washed with water, and welldried. When the dye solution was not effectively removed by water, 1%acetic acid was used. 150 μl of 10 mM trisma base was added to eachwell, and the absorbance at 540 nm wavelength was determined with amicroplate reader. In case of NCI-H1975, the cell viabilities weredetermined as the absorbance at 490 nm wavelength using Celltiter 96Aqueous One solution (MTS, promega).

GI₅₀, the concentration at which 50% inhibition occurs, was evaluatedbased on the difference between the final density of the test cells andthe initial density of the cells incubated in a well not-treated withthe test compound which was regarded as 100%. The calculation of GI₅₀and the result analysis were carried out by using Microsoft Excel, andthe results are shown in Tables 14a to 14f. Wherein, A means thatGI₅₀≦50 nM, B means that GI₅₀ is 50-100 nM, C means that GI₅₀ is100-1,000 nM, and D means that GI₅₀≧1,000 nM.

TABLE 14a GI₅₀ HCC827 NCI-H1975 A431 Example EGFR DelE746_A750 EGFRL858R/T790M EGFR WT 1 A A D 2 B B D 3 A A D 4 B B D 6 B A — 7 A A — 8 AA D 9 A A — 10 A A C 11 A A C 12 A A — 13 A A C 14 A B — 15 A A — 16 B A— 17 A A — 18 A A — 22 A B — 23 B A D 24 A B D 25 B B — 26 A A D 27 A A— 28 B A — 29 B A D 30 C A D 31 A A D 32 A A D 35 A A — 36 B A —

TABLE 14b GI₅₀ HCC827 NCI-H1975 A431 Example EGFR DelE746_A750 EGFRL858R/T790M EGFR WT 37 C A D 38 A A — 40 A B 41 A A — 42 A A D 45 A A —46 A A — 47 A A — 48 A A D 49 A A — 50 A C D 51 A A D 52 A A D 53 A A D54 A A D 55 A A — 56 B A — 57 A C — 59 A C — 60 C C — 61 B A — 62 A A D65 A A D 66 A A D 69 B A — 71 B A — 72 A A — 76 A B D 77 A A — 78 B B —79 A C — 80 A A D

TABLE 14c GI₅₀ HCC827 NCI-H1975 A431 Example EGFR DelE746_A750 EGFRL858R/T790M EGFR WT 82 A A D 83 A A C 84 B B — 90 A A D 92 A A — 93 B B— 94 A A D 95 A A — 97 B A — 98 A A — 99 B A D 100 A A D 102 A B — 103 CA — 106 B A — 107 A A D 108 B B — 109 A A D 111 B A — 112 A A D 114 B A— 115 A A — 116 A A — 117 A B — 118 A B — 119 A A — 120 A A D 121 B A —122 A A D 123 B B — 124 A A — 125 A A D

TABLE 14d GI₅₀ HCC827 NCI-H1975 A431 Example EGFR DelE746_A750 EGFRL858R/T790M EGFR WT 126 A A — 127 A A — 128 A A D 129 A A D 130 A A —131 B A — 132 A A — 133 A A — 134 A A — 135 B A — 136 A A — 138 A A —139 A A — 140 B B — 142 A A D 143 B A — 144 A B — 148 A A — 154 B B —156 A B — 158 A C D 159 A A D 160 A A — 165 A A D 167 A A D 168 A A D169 A B — 172 B A — 173 A A C 174 A A — 175 A A — 176 A A D

TABLE 14e GI₅₀ HCC827 NCI-H1975 A431 Example EGFR DelE746_A750 EGFRL858R/T790M EGFR WT 178 A A D 180 A A D 181 A A D 182 A A D 183 A A D184 A A D 185 A A D 186 A A D 187 B A D 189 A A D 190 A A — 191 A A —196 A B — 197 A A — 199 A A D 201 A B — 202 B A — 203 A A D 205 A A —206 A A D 207 A A — 208 A A — 209 A A — 210 A A — 211 A A — 212 B B —213 B A — 214 B A — 215 A A — 216 A A — 217 A B — 218 A B D

TABLE 14f GI₅₀ HCC827 NCI-H1975 A431 Example EGFR DelE746_A750 EGFRL858R/T790M EGFR WT 219 A A D 220 A A — 221 A A — 222 B B — 223 A A D224 A A — 225 A A — 228 A A C 229 A A C 232 B B — 234 A A D 235 A A —237 A A D Erlotinib A D B Lapatinib C D B BIBW2992 A A A

As shown in Tables 14a to 14f, almost of the inventive compounds showedan excellent anticancer activity by selectively inhibiting the growth ofthe HCC827 and NCI-H1975 non-small cell lung cancer (NSCLC) cellsexpressing EGFR mutants (GI₅₀=A or B), with no anticancer activity onA431 cell expressing EGFR WT (GI₅₀=D). Such the inhibition mechanisms ofthe inventive compounds are very different from those of thecommercially marketable EGFR tyrosine kinases (e.g., Erlotinib andLapatinib) or the being developed material (BIBW2992).

As shown in Table 14f, Erlotinib as the first generation EGFR inhibitorwas very effective in inhibiting the growth of NSCLC cell linesexpressing EGFR mutants (HCC827, GI₅₀=A), while it provided noinhibition activity against NSCLC cell lines expressing EGFR T790M pointmutation (NCI-H1975, GI₅₀=D). Also, the currently marketable Lapatinibwhich inhibits both EGFR and HER-2 showed a weak inhibition activity(HCC827, GI₅₀=C) or no inhibition activity (NCI-H1975, GI₅₀=D) againstNSCLC cell lines. Further, the irreversible inhibitor having quinazolinestructure, BIBW2992 (Boehringer Ingelheim, currently in the phase IIIstage, exhibited a strong inhibition activity against pan-HER andeffectively inhibited all the cancer cell lines disclosed in Tables 14ato 14f including A431 cell line (GI₅₀=A). However, such irreversibleinhibitor having the quinazoline structure may cause serious adverseside effects (e.g., diarrhea, skin rash and weight loss) when treated inan amount for inhibiting EGFR T790M, and therefore, there still has beena need to develop a safe drug for overcoming the problems of theresistance development of EGFR T790M. Therefore, the inventive compoundsshowed a highly improved inhibition activity against EGFR mutantsincluding EGFR T790M, with no inhibition activity against EGFR WTexpressed in normal cell, which suggests that the inventive compoundscan be used as more effective and safe anticancer drugs to NSCLCpatients.

Test Example 2 Inhibition Test for Activities of EGFR WT and L858R/T790MKinase

The inhibiting activities of the inventive compounds obtained inExamples 1 to 237 against EGFR WT and EGFR L858R/T790M kinase weredetermined using z-lyte kinase assay kit (Invitrogen, PV3191). Thekinases used in the test were purchased from Invitrogen.

The compounds obtained in Examples 1 to 237 were each prepared to 10 mMDMSO solution, and a solution containing 4% DMSO were prepared therefromand diluted to a concentration of 1 μM to 0.0001 μM. Then, anapproximate Kd value of each kinase was calculated, and diluted using akinase buffer (50 mM HEPES (PH 7.4), 10 mM MgCl₂, 1 mM EGTA and 0.01%BRIJ-35) to 1 to 100 ng/assay concentration. The test was conducted in a384 well polystyrene flat-bottomed plates. 5 μl of the diluted solutionof each compound was added to each well, and 10 μl of a mixture ofpeptide substrate and kinase in a suitable concentration and 5 μl of5-300 μM ATP solution were successively added thereto and the plate wasincubated in a stirrer at room temperature for 60 minutes. After 60mins, 10 μl of coloring reagent was added to the resulting mixture toinitiate a fluorescence reaction of peptide substrate and a terminatingsolution was added thereto for terminating the reaction. A fluorescencevalue of each well was determined with a fluorescence meter (MolecularDevice) at 400 nm (excitation filter) and 520 nm (emission filter). Theinhibiting activity of the test compounds against the kinases wasdetermined as a phosphorylation percentage (%) compared with controlgroup, according to the kit protocol, and measured for IC₅₀, theconcentration of x-axis at which 50% inhibition was observed. Thecalculation of IC₅₀ and the result analysis were carried out by usingMicrosoft Excel. The results are shown in Table 15. Wherein, A meansthat IC₅₀≦50 nM, B means that IC₅₀ is 50-100 nM, C means that IC₅₀ is100-1,000 nM, and D means that IC₅₀≧1,000 nM.

TABLE 15 IC₅₀ Example EGFR WT EGFR L858R/T790M 1 C A 2 D A 48 C A 115 DA 122 D A 206 C A 215 D A Erlotinib A C Lapatinib B D BIBW2992 A A

As shown in Table 15, the inventive compounds showed a relatively lowinhibition activity against EGFR WT related with the adverse effects(IC₅₀=C or D), while it showed an excellent inhibition activity againstEGFR L858R/T790M mutants having a resistance to the commerciallymarketable EGFR inhibitors (IC₅₀=A). Like the results from Test Example1, such the inhibition mechanisms of the inventive compounds are verydifferent from those of the commercially marketable EGFR tyrosinekinases (e.g., Erlotinib and Lapatinib) or the being developed material(BIBW2992) which strongly inhibit EGFR WT (IC₅₀=A or B). Therefore, theinventive compounds are effective and safe drug employable to NSCLCpatients by showing an effectively excellent inhibition activity againstEGFR mutants including EGFR T790M with no inhibition activity againstEGFR WT expressed in normal cell.

Test Example 3 Inhibition Test for Activities of BTK and JAK3 Kinase

The inhibiting activities of the inventive compounds obtained inExamples 1 to 237 against BTK and JAK3 kinases were determined,respectively. The procedure of Test Example 2 was repeated except thatBTK and JAK3 kinases (Invitrogen) were employed instead of using theEGFR kinase. The results are shown in Tables 16a to 16c. Wherein, Ameans that IC₅₀≦50 nM, B means that IC₅₀ is 50-100 nM, C means that IC₅₀is 100-1,000 nM, and D means that IC₅₀≧1,000 nM.

TABLE 16a IC₅₀ Example BTK JAK3 1 A A 3 A B 7 A B 9 A A 11 A A 21 A B 28A A 29 A A 36 B B 40 B B 41 B B 42 A B 44 B B 47 B B 48 A A 50 A B 51 AB 53 A A 55 B A 57 A B 59 A B 62 A A 66 A B 67 A A 68 B A 70 A A 72 A A73 A B 74 A B 79 A A

TABLE 16b IC₅₀ Example BTK JAK3 82 A A 83 A A 85 A A 88 B B 89 A B 91 AB 95 B B 99 A B 103 A A 104 A A 105 B A 125 A A 127 B B 129 A A 130 B A141 A B 142 A A 145 A A 146 B B 148 A B 151 B B 152 A B 154 A B 169 A B173 A A 174 A B 177 A A 179 A A 180 A A 181 A A

TABLE 16c IC₅₀ Example BTK JAK3 182 A B 183 B B 187 B B 199 A A 203 A B219 A A 223 A A 228 A A 229 A A 232 A A 233 A A 237 A A

As shown in Tables 16a to 16c, the inventive compound showed anexcellent inhibition activity against BTK and JAK kinases (IC₅₀=A or B).

Test Example 4 Inhibition Test for Activities of BMX, ITX and RLKKinases

The compound obtained in Example 1 was measured for its inhibitoryactivity on TEC family kinases, i.e., BMX, ITK, TEX and RLK. Themeasurement was carried out in the same process as in Example 2, exceptfor using BMX, ITK, TEC and RLK enzymes (Invitrogen) instead of EGFRenzyme. The results are shown in Table 17. The letter ‘A’ in the tablemeans IC₅₀≦50 nM, ‘B’ means IC₅₀=50-100 nM, ‘C’ means IC₅₀=100-1,000 nM,and ‘D’ means IC₅₀≧1,000 nM.

TABLE 17 IC₅₀ Example BMX ITK RLK 1 A B A

As shown in Table 17, the compound of Example 1 according to the presentinvention effectively inhibited TEC family kinases such as BTK, BMX,ITK, and RLK kinases (IC₅₀=A or B).

Test Example 5 Anticancer Efficacy Test in Nude Mice Xenografted withNCI-H1975 Cancer Cells

The compound according to the present invention (Example 2) was testedfor its anticancer effect and toxicity in nude mice xenografted withNCI-H1975 cancer cells which shows resistance to Erlotinib previouslyapproved for the treatment of non-small cell lung cancer, due to theacquisition of EGFR T790M point mutation. In order to evaluate theanticancer efficacy and toxicity of the compound according to thepresent invention, BIBW2992 (Boehringer Ingelheim), which currentlyexhibits excellent activity to resistant non-small cell lung cancer andis actively under development, was also used in the test.

NCI-H1975 cell (lung cancer cell) was purchased from American TypeCulture Collection (ATCC). After formation of tumor by subcutaneousinjection with 1×10⁸ cells/0.3 mL of tumor cell suspension on the backof mice, passages were carried out and tumor in at least thirdgeneration was used in the test.

In the test, a tumor in the sixth generation isolated from an individualwas cut into a size of 30 mg, and transplanted subcutaneously into rightflanks of mice using a 12-gauge trocar. The volume of tumor (V) iscalculated from following equation 1 after measuring a long diameter (L)and a short diameter (S) using a vernier caliper twice a week for 18days of test. All test materials were orally administered one time a dayfor total 10 days, and the tumor growth inhibition rate (IR: tumorgrowth inhibition rate (%) calculated based on a vehicle-treatedcontrol) and the maximum body weight loss (mBWL: maximum body weightloss calculated based on the body weight just before administration)were calculated using following equations 2 and 3. The results are shownin Table 6 and FIGS. 1 and 2.V=L×S ²/2  <Equation 1>

wherein, L is a long diameter and S is a short diameter.IR (%)=(1−(RTG of the treatment group of test material)/(RTG of thecontrol group))×100  <Equation 2>

wherein, RTG is a relative tumor growth, which is the mean tumor volumeon a particular day based on daily mean tumor volume.mBWL (%)=(1−(mean body weight on day x/mean body weight just beforeadministration))×100  <Equation 3>

wherein, day x is a day on which the body weight loss is largest duringthe test.

Following Table 18 is the results of IR and mBWL in an NCI-H1975 in vivomodel.

TABLE 18 Compound BIBW2992 Example 2 Dose 50 mg/kg 70 mg/kg IR¹⁾ 77% 75%mBWL²⁾ 9.1%  −7.6%    ¹⁾measured on 16^(th) day after administration;²⁾measured on 10^(th) day after administration.

The compound of the present invention did not inhibit EGFR WT andexhibited an excellent activity on EGFR mutant specific to non-smallcell lung cancer (active mutant: EGFR DelR746_A750, EGFR L858R; acquiredmutation: EGFR T790M). As shown in Table 18 and FIGS. 1 and 2, EGFRinhibitors exhibited comparable efficacies to BIBW2992 in NCI-H1975, ananimal model which is the most difficult to show the efficacy (IR=77% vs75%), while it did not exhibit any adverse side effects resulted fromthe pharmacological actions such as dermatologic diseases and bodyweight loss (BIBW2992: 9.1% of weight loss, Example 2: 7.6% of weightgain in therapeutically equivalent dose). These experimental resultsshow that the compounds according to the present invention selectivelyand effectively inhibit the growth of cancer and the resistance to drugcaused by the mutation of EGFR while showing no adverse side effects.

Test Example 6 Inhibition on Collagen-Induced Arthritis in Mice

In order to evaluate the efficacy of the compound according to thepresent invention for rheumatoid arthritis, the compound was subjectedto arthritis inhibition test in a collagen-induced arthritis (CIA)model. The CIA model is a widely used, representative autoimmunearthritis model, arthritis of which is induced by injecting a mixture oftype II collagen and an immunologic adjuvant to a specific mouse strainhaving major histocompatability complex (MHC) class II with H-2^(q) orH-2^(r) and thus CD4+ T cells and B-cells specifically responsive to thetype II collagen are abnormally activated.

Male DBA/1J mice (8 weeks old) were first immunized by intradermalinjection of 0.7 mL of a suspension liquid in which an equal volume of 2mg/mL of type II collagen is emulsified in 4 mg/mL of complete Freund'sadjuvant supplemented with bacteria tuberculosis. After 21 days, themice were second immunized by the injection as above, except for using asuspension liquid in which an equal volume of 2 mg/mL of type IIcollagen is emulsified in incomplete Freund's adjuvant containing nobacteria tuberculosis. After 1 week of second immunization, mice wereevaluated for clinical scores based on Table 19 and seven animals weregrouped such that the average of experimental group is between 1 and 2.Test samples and vehicle of given concentrations were orallyadministered in an amount of 10 mL per body weight for 14 days everydayby using a Sonde. The clinical scores of arthritis (David D Brand etal., Nature Protocol. 2(5), 1269, 2007) were evaluated three times aday.

The compound of Example 1 reduced edema and flare until the last day (14days) of the test in 10 mg/kg and 30 mg/kg groups compared to a controlgroup, and significantly reduced edema, inflammation and flare in a 30mg/kg group (FIG. 3).

As shown in Tables 16a, 16b and 16c and FIG. 3, the compound accordingto the present invention inhibited the activities of BTK and JAK3kinases, and the inhibitions reduced edema, inflammation and flare aswell as anti-collagen antibody values in a CIA model of autoimmunearthritis, compared to a control group, and also reduced the formationof pannus in histopathologic testing. The above results in a rodentmodel of arthritis suggest that the compound according to the presentinvention may provide clinical effects for patients with rheumatoidarthritis.

In addition, the compound according to the present inventionsignificantly reduced the secretion of interleukin-6 (IL-6) and TNF-α inhuman peripheral blood mononuclear cells (PBMCs) and mouse splenocytesabundant in T-lymphocytes, B-lymphocytes, Cytes and macrophages aftertreatment of phorbol-12-myristate-13-acetate (PMA), phytohemagglutinin(PHA), lonomycin, and others which stimulate lymphocytes, compared to acontrol group. This demonstrates that the compound according to thepresent invention inhibits the activation of lymphocytes.

TABLE 19 Evaluation of clinical scores of arthritis Rate Characteristics0 No edema and flare in paws, ankles, and ankle joints 1 Flare and mildedema in ankles or ankle joints 2 Flare and mild edema generally fromankle joints to ankles 3 Flare and edema from ankle joints to toe joints4 Severe edema or spastic tetraplegia in overall joints, paws and toes

While the invention has been described with respect to the abovespecific embodiments, it should be recognized that various modificationsand changes may be made to the invention by those skilled in the artwhich also fall within the scope of the invention as defined by theappended claims.

What is claimed is:
 1. A compound of formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein, W is O; X is O, NH, S, SO or SO₂; Y is hydrogen atom, halogenatom, C₁₋₆alkyl or C₁₋₆alkoxy; A and B are each independently hydrogenatom, halogen atom, or di(C₁₋₆alkyl)aminomethyl; Z is selected from thegroup consisting of formulae Z1 to Z203:


2. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein, W is O; X is O; Y is hydrogen; and A and B are eachindependently hydrogen.
 3. A compound of formula (I) or apharmaceutically acceptable salt thereof:

wherein, W is O; X is O; Y is hydrogen; A and B are each independentlyhydrogen; and Z is selected from the group consisting of formulae Z2,Z4, Z28, Z61, Z100, Z113, Z138, Z164, Z168 and Z189:


4. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 5. A compound of theformula:

or a pharmaceutically acceptable salt thereof.
 6. A compound of theformula:


7. A method of inhibiting epidermal growth factor receptor (EGFR)tyrosine kinase, Bruton's tyrosine kinase (BTK), EGFR L858R/T790Mmutant, janus kinase 3 (JAK3), interleukin-2 inducing T-cell kinase(ITK), resting lymphocyte kinase (RLK), and/or bone marrow tyrosinekinase (BMX), comprising administering to a mammal in need thereof atherapeutically effective amount of a compound of formula (I) or itspharmaceutically acceptable salt of claim 1, wherein the mammal issuffering from cancer, tumor, inflammatory disease, autoimmune disease,or immunologically mediated disease.
 8. A method of inhibiting epidermalgrowth factor receptor (EGFR) tyrosine kinase, Bruton's tyrosine kinase(BTK), EGFR L858R/T790M mutant, janus kinase 3 (JAK3), interleukin-2inducing T-cell kinase (ITK), resting lymphocyte kinase (RLK), and/orbone marrow tyrosine kinase (BMX), comprising administering to a mammalin need thereof a therapeutically effective amount of a compound offormula (I) or its pharmaceutically acceptable salt of claim 2, whereinthe mammal is suffering from cancer, tumor, inflammatory disease,autoimmune disease, or immunologically mediated disease.
 9. A method ofinhibiting epidermal growth factor receptor (EGFR) tyrosine kinase,Bruton's tyrosine kinase (BTK), EGFR L858R/T790M mutant, janus kinase 3(JAK3), interleukin-2 inducing T-cell kinase (ITK), resting lymphocytekinase (RLK), and/or bone marrow tyrosine kinase (BMX), comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of a compound of formula (I) or its pharmaceutically acceptablesalt of claim 3, wherein the mammal is suffering from cancer, tumor,inflammatory disease, autoimmune disease, or immunologically mediateddisease.
 10. The method according to claim 7, wherein the cancer ortumor is induced by EGFR tyrosine kinase or EGFR L858R/T790M mutant. 11.The method of claim 7, wherein the mammal in need thereof suffers fromcancer, tumor, inflammatory disease, autoimmune disease, orimmunologically mediated disease that is mediated by at least one kinaseselected from the group consisting of BTK, JAK3, ITK, RLK, and BMX. 12.The method of claim 7, wherein the mammal in need thereof suffers fromcancer, tumor, inflammatory disease, autoimmune disease, orimmunologically mediated disease that is mediated by abnormallyactivated B-lymphocytes, T-lymphocytes or both.
 13. The method of claim7, wherein the inflammatory disease, autoimmune disease, orimmunologically mediated disease is arthritis, rheumatoid arthritis,spondyloarthropathy, gouty arthritis, osteoarthritis, juvenilearthritis, other arthritic condition, lupus, systemic lupuserythematosus (SLE), skin-related disease, psoriasis, eczema,dermatitis, atopic dermatitis, pain, pulmonary disorder, lunginflammation, adult respiratoty distress syndrome (ARDS), pulmonarysarcoidosis, chronic pulmonary inflammatory disease, chronic obstructivepulmonary disease (COPD), cardiovascular disease, artherosclerosis,myocardial infarction, congestive heart failure, cardiac reperfusioninjury, inflammatory bowl disease, Crohn's disease, ulcerative colitis,irritable bowl syndrome, asthma, sjogren syndrome, autoimmunity thyroiddisease, urticaria (cnidosis), multiple sclerosis, scleroderma, organtransplantation rejection, heteroplastic graft, idiopathicthrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer'sdisease, diabetic associated disease, inflammation, pelvic inflammatorydisease, allergic rhinitis, allergic bronchitis, allergic sinusitis,leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acutelymphoid leukemia (ALL), chronic lymphoid leukemia (CLL), acute myeloidleukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia,Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma,myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN),diffuse large B-cell lymphoma, or follicular lymphoma.
 14. The method ofclaim 7, wherein the compound of formula (I) or its pharmaceuticallyacceptable salt is administered in combination with an anticancer agentselected from the group consisting of: cell signal transductioninhibitors, mitosis inhibitors, alkylating agents, intercalatinganticancer agents, topoisomerase inhibitors, immunotherapic agents,antihormonal agents, and a mixture thereof.
 15. The method of claim 7,wherein the compound of formula (I) or its pharmaceutically acceptablesalt is administered in combination with a therapeutic agent selectedfrom the group consisting of: steroid drugs, methotrexates,leflunomides, anti-TNFα agents, calcineurin inhibitors, antihistaminicdrugs, and a mixture thereof.
 16. The method according to claim 8,wherein the cancers or tumors are induced by EGFR tyrosine kinase orEGFR L858R/T790M mutant.
 17. The method of claim 8, wherein the mammalin need thereof suffers from cancer, tumor, inflammatory disease,autoimmune disease, or immunologically mediated disease that is mediatedby at least one kinase selected from the group consisting of BTK, JAK3,ITK, RLK, and BMX.
 18. The method of claim 8, wherein the mammal in needthereof suffers from cancer, tumor, inflammatory disease, autoimmunedisease, or immunologically mediated disease that is mediated byabnormally activated B-lymphocytes, T-lymphocytes or both.
 19. Themethod of claim 8, wherein the inflammatory disease, autoimmune disease,or immunologically mediated disease is arthritis, rheumatoid arthritis,spondyloarthropathy, gouty arthritis, osteoarthritis, juvenilearthritis, other arthritic condition, lupus, systemic lupuserythematosus (SLE), skin-related disease, psoriasis, eczema,dermatitis, atopic dermatitis, pain, pulmonary disorder, lunginflammation, adult respiratoty distress syndrome (ARDS), pulmonarysarcoidosis, chronic pulmonary inflammatory disease, chronic obstructivepulmonary disease (COPD), cardiovascular disease, artherosclerosis,myocardial infarction, congestive heart failure, cardiac reperfusioninjury, inflammatory bowl disease, Crohn's disease, ulcerative colitis,irritable bowl syndrome, asthma, sjogren syndrome, autoimmunity thyroiddisease, urticaria (cnidosis), multiple sclerosis, scleroderma, organtransplantation rejection, heteroplastic graft, idiopathicthrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer'sdisease, diabetic associated disease, inflammation, pelvic inflammatorydisease, allergic rhinitis, allergic bronchitis, allergic sinusitis,leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acutelymphoid leukemia (ALL), chronic lymphoid leukemia (CLL), acute myeloidleukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia,Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma,myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN),diffuse large B-cell lymphoma, or follicular lymphoma.
 20. The method ofclaim 8, wherein the compound of formula (I) or its pharmaceuticallyacceptable salt is administered in combination with an anticancer agentselected from the group consisting of: cell signal transductioninhibitors, mitosis inhibitors, alkylating agents, intercalatinganticancer agents, topoisomerase inhibitors, immunotherapic agents,antihormonal agents, and a mixture thereof.
 21. The method of claim 8,wherein the compound of formula (I) or its pharmaceutically acceptablesalt is administered in combination with a therapeutic agent selectedfrom the group consisting of: steroid drugs, methotrexates,leflunomides, anti-TNFα agents, calcineurin inhibitors, antihistaminicdrugs, and a mixture thereof.
 22. The method according to claim 9,wherein the cancer or tumor is induced by EGFR tyrosine kinase or EGFRL858R/T790M mutant.
 23. The method of claim 9, wherein the mammal inneed thereof suffers from cancer, tumor, inflammatory disease,autoimmune disease, or immunologically mediated disease that is mediatedby at least one kinase selected from the group consisting of BTK, JAK3,ITK, RLK, and BMX.
 24. The method of claim 9, wherein the mammal in needthereof suffers from cancer, tumor, inflammatory disease, autoimmunedisease, or immunologically mediated disease that is mediated byabnormally activated B-lymphocytes, T-lymphocytes or both.
 25. Themethod of claim 9, wherein the inflammatory disease, autoimmune disease,or immunologically mediated disease is arthritis, rheumatoid arthritis,spondyloarthropathy, gouty arthritis, osteoarthritis, juvenilearthritis, other arthritic condition, lupus, systemic lupuserythematosus (SLE), skin-related disease, psoriasis, eczema,dermatitis, atopic dermatitis, pain, pulmonary disorder, lunginflammation, adult respiratoty distress syndrome (ARDS), pulmonarysarcoidosis, chronic pulmonary inflammatory disease, chronic obstructivepulmonary disease (COPD), cardiovascular disease, atherosclerosis,myocardial infarction, congestive heart failure, cardiac reperfusioninjury, inflammatory bowl disease, Crohn's disease, ulcerative colitis,irritable bowl syndrome, asthma, sjogren syndrome, autoimmunity thyroiddisease, urticaria (cnidosis), multiple sclerosis, scleroderma, organtransplantation rejection, heteroplastic graft, idiopathicthrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer'sdisease, diabetic associated disease, inflammation, pelvic inflammatorydisease, allergic rhinitis, allergic bronchitis, allergic sinusitis,leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acutelymphoid leukemia (ALL), chronic lymphoid leukemia (CLL), acute myeloidleukemia (AML), chronic myeloid leukemia (CML), hairy cell leukemia,Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma,myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN),diffuse large B-cell lymphoma, or follicular lymphoma.
 26. The method ofclaim 9, wherein the compound of formula (I) or its pharmaceuticallyacceptable salt is administered in combination with an anticancer agentselected from the group consisting of: cell signal transductioninhibitors, mitosis inhibitors, alkylating agents, intercalatinganticancer agents, topoisomerase inhibitors, immunotherapic agents,antihormonal agents, and a mixture thereof.
 27. The method of claim 9,wherein the compound of formula (I) or its pharmaceutically acceptablesalt is administered in combination with a therapeutic agent selectedfrom the group consisting of: steroid drugs, methotrexates,leflunomides, anti-TNFα agents, calcineurin inhibitors, antihistaminicdrugs, and a mixture thereof.
 28. A pharmaceutical compositioncomprising a compound of any one of claims 1-4 and a pharmaceuticalcarrier.
 29. A pharmaceutical composition comprising a compound of theformula:

or a pharmaceutically acceptable salt thereof, and a pharmaceuticalcarrier.
 30. A method of treating rheumatoid arthritis comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of a compound of the formula:

or a pharmaceutically acceptable salt thereof.
 31. A method of treatingsjogren syndrome comprising administering to a mammal in need thereof atherapeutically effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof.